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| Intellectual disability - microarray and sequencing v5.490 | SRPX2 | Arina Puzriakova Phenotypes for gene: SRPX2 were changed from Rolandic epilepsy, mental retardation, and speech dyspraxia, 300643 -3; ROLANDIC EPILEPSY WITH SPEECH DYSPRAXIA AND MENTAL RETARDATION X-LINKED (RESDX) to ?Rolandic epilepsy, impaired intellectual development, and speech dyspraxia, OMIM:300643 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.451 | MADD | Sarah Leigh Phenotypes for gene: MADD were changed from Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 to DEEAH syndrome, OMIM:619004; deeah syndrome, MONDO:0033561: Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, OMIM:619005; neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, MONDO:0033562 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.445 | ABCC9 | Sarah Leigh changed review comment from: Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872).; to: Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872). Heterozygous parents of the cases, did not show a consistent phenotype, although intrauterine death was reported in two families (PMID: 38217872). In family 4 the fetus was homozygous for c.1858C>T, p.(Arg620Ter) and in family 8 the parents were both heterozygous for c.2140_2141del, p.(Leu714SerfsTer7), but analysis of the fetus was not possible. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.389 | CLDN11 |
Achchuthan Shanmugasundram gene: CLDN11 was added gene: CLDN11 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CLDN11 were set to 33313762 Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328 Review for gene: CLDN11 was set to GREEN Added comment: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. These patients exhibit global developmental delay, particularly motor and speech delay. Intellectual disability was maximally mild in two of three individuals and the intelligence is in a low-normal range in third individual, although IQ testing was not performed in them. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes global developmental delay and impaired intellectual development (mild) as clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.362 | C20orf24 |
Arina Puzriakova Added comment: Comment on list classification: New gene added by Hannah Knight. Biallelic LoF variant identified in a patient with craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome. Authors suggested possible low penetrance due to two relatives with heterozygous variant and cleft lip and/or palate (PMID: 35614220). Rating Red as only a single family reported to date. In OMIM the relationship between the phenotype and gene is provisional. |
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| Intellectual disability - microarray and sequencing v5.361 | C20orf24 | Arina Puzriakova Phenotypes for gene: C20orf24 were changed from ?Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2 to ?Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2, OMIM:616994 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.347 | PSMC3 |
Achchuthan Shanmugasundram changed review comment from: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts. PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program. The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.; to: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. They were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts. PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program. The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources. |
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| Intellectual disability - microarray and sequencing v5.347 | PSMC3 |
Achchuthan Shanmugasundram changed review comment from: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts. PMID:37256937 - 23 individuals with neurodevelopmental disorder was identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program. The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.; to: PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. There were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts. PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program. The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources. |
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| Intellectual disability - microarray and sequencing v5.341 | C20orf24 |
Hannah Knight gene: C20orf24 was added gene: C20orf24 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: C20orf24 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C20orf24 were set to 35614220 Phenotypes for gene: C20orf24 were set to ?Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2 Added comment: HGNC Approved Gene Symbol: RAB5IF PMID: 35614220 (2022) identified a homozygous nonsense variant (p.W25X) in a Turkish boy previously reported by PMID: 24194475 to have bilateral cleft lip, complete cleft palate, moderate to severe intellectual delay and dysmorphic features. FHx of cleft lip/cleft palate as well in relatives who were heterozygous for the reported variant Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.332 | AGPAT3 |
Zornitza Stark gene: AGPAT3 was added gene: AGPAT3 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: AGPAT3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGPAT3 were set to 37821758 Phenotypes for gene: AGPAT3 were set to Neurodevelopmental disorder (MONDO#0700092), AGPAT3-related Review for gene: AGPAT3 was set to AMBER Added comment: - Single consanguineous family with four individuals with severe intellectual disability and retinitis pigmentosa - All affected individuals were homozygous for a nonsense variant in AGPAT3, healthy unaffected individuals who were tested were heterozygous for the variant - Overexpression of mutant transcript revealed absence of AGPAT3 protein compared to WT transcript via Western blot analysis - KO AGPAT3 mouse demonstrated impaired neuronal migration Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.303 | UBAP2L | Arina Puzriakova Phenotypes for gene: UBAP2L were changed from Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system to Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies, OMIM:620494 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.257 | ATP6V0C |
Achchuthan Shanmugasundram changed review comment from: 17 of 32 total patients had impaired intellectual development.; to: PMID:36074901 - 16 of 27 patients identified with monoallelic ATP6V0C variants, including a patient each from PMID:24623842 and PMID:33190975 had impaired intellectual development, while 21 patients had developmental delay. PMID:37161035 - One of three patients identified with monoallelic ATP6V0C variant had impaired intellectual development and language delay, while another had developmental delay and speech delay. This gene has been associated with relevant phenotypes in OMIM (MIM #620465) and Gene2Phenotype (with 'strong' rating in the DD panel). |
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| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.242 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.241 | PSMC3 | Achchuthan Shanmugasundram Phenotypes for gene: PSMC3 were changed from neurodevelopmental delay to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.239 | PSMC3 | Achchuthan Shanmugasundram reviewed gene: PSMC3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32500975, 37256937; Phenotypes: ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.234 | LETM1 |
Sarah Leigh changed review comment from: LETM1 variants has been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder. PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder. PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c). |
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| Intellectual disability - microarray and sequencing v5.224 | AGTPBP1 |
Achchuthan Shanmugasundram changed review comment from: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype. This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating). Sources: Literature; to: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype. This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating). Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.224 | AGTPBP1 |
Achchuthan Shanmugasundram changed review comment from: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe, and several patients were unable to speak or have eye contact. This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating). Sources: Literature; to: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe in several patients: Two had severe cognitive delay, one had profound cognitive delay, five had no speech and four had no visual recognition. In addition, functional studies with mouse models have recapitulated the human phenotype. This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating). Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.224 | AGTPBP1 |
Achchuthan Shanmugasundram gene: AGTPBP1 was added gene: AGTPBP1 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: AGTPBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AGTPBP1 were set to 30420557 Phenotypes for gene: AGTPBP1 were set to Neurodegeneration, childhood-onset, with cerebellar atrophy, OMIM:618276 Review for gene: AGTPBP1 was set to GREEN Added comment: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Impaired intellectual development was severe, and several patients were unable to speak or have eye contact. This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating). Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.166 | CLDN5 |
Achchuthan Shanmugasundram changed review comment from: PMID: 36477332 identified de novo heterozygous missense variants in CLDN5 in fifteen unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. Sources: Literature; to: PMID:36477332 reported the identification of de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a number of clinical features including developmental delay including intellectual disability, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognisable pattern of pontine atrophy and brain calcifications. All seven living patients over four years of age were reported to have intellectual disability. In addition, functional studies from zebrafish model also provided parallel evidence that CLDN5 variants cause a neurodevelopmental disorder involving disruption of the blood brain barrier and impaired neuronal function. This gene has been associated with relevant phenotypes in Gene2Phenotype (CLDN5-related neurodevelopmental disorder with 'limited' rating in the DD panel), but not in OMIM. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.115 | CHMP3 |
Arina Puzriakova gene: CHMP3 was added gene: CHMP3 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHMP3 were set to 35710109 Phenotypes for gene: CHMP3 were set to Complex spastic quadriplegia associated with developmental delay and seizures Added comment: Cohen-Barak et al., 2022 (PMID: 35710109) reported on a consanguineous family, in which five individuals presented with intellectual and progressive motor disabilities, seizures and spastic quadriplegia, associated with a homozygous variant in CHMP3. Patient derived fibroblasts expressed ultrastructural and molecular features of impaired autophagy, partially rescued by ectopic expression of WT-CHMP3. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.93 | PPFIBP1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 (16 individuals from 12 families) shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16). This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel).; to: As reviewed by Konstantinos Varvagiannis, all individuals (16 individuals from 12 families) reported in PMID:35830857 shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16). This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel). |
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| Intellectual disability - microarray and sequencing v5.93 | PPFIBP1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16). This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel).; to: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 (16 individuals from 12 families) shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16). This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel). |
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| Intellectual disability - microarray and sequencing v5.90 | PPFIBP1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16).; to: As reviewed by Konstantinos Varvagiannis, all individuals reported in PMID:35830857 shared a core phenotype of global developmental delay/intellectual disability (GDD/ID) and epilepsy. 15 were affected by profound or severe GDD/ID (15/16). They had not acquired speech (15/16) and showed impaired motor development (15/16). This gene has already been associated with relevant phenotypes in both OMIM (MIM #620024) and Gene2Phenotype (with 'strong' rating in the DD panel). |
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| Intellectual disability - microarray and sequencing v5.70 | INTS11 |
Achchuthan Shanmugasundram changed review comment from: PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy. Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Sources: Literature; to: PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy. Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.68 | INTS11 |
Achchuthan Shanmugasundram gene: INTS11 was added gene: INTS11 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: INTS11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INTS11 were set to 37054711 Phenotypes for gene: INTS11 were set to intellectual disability, MONDO:0001071 Review for gene: INTS11 was set to GREEN Added comment: PMID:37054711 reported ten unrelated families with biallelic variants in INTS11 gene and they present with intellectual disability, global developmental and language delay, impaired motor development, and brain atrophy. Functional studies in Drosophila showed that dIntS11 (fly ortholog of INTS11) is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. In addition, genes with two variants (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants in the Drosophila model, indicating that they are strong loss-of-function variants. The other five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Sources: Literature |
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| Intellectual disability - microarray and sequencing v5.50 | OTUD7A |
Achchuthan Shanmugasundram changed review comment from: PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe). PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11. PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion. OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome.; to: PMID:31997314 reported a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy and was identified with homozygous variant in OTUD7A gene (c.697C>T)/ p.Leu233Phe). PMID:33381903 reported a patient with profound hypotonia, severe intellectual disability, and seizures and identified with biallelic loss-of-function variants in OTUD7A: a 15q13.3 deletion including the OTUD7A locus, and a frameshift OTUD7A variant c.1125del/ p.Glu375Aspfs*11. PMID:36180924 reported a patient (patient #4) presenting with severe neurodevelopmental diseases and dysmorphic features and identified with hemizygous OTUD7A frameshift variant allele c.2023_2066del/ p.D675Hfs*188 in trans with the recurrent 15q13.3 BP4-BP5 deletion. OTUD7A knockout mice exhibited reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalisations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle (PMID:29395075). The function evidence also suggest that OTUD7A may be the critical “driver gene” in the 15q13.3 deletion syndrome. This gene has been reported in the DD panel of Gene2Phenotype (with 'limited' rating), but has not yet been associated with phenotypes in OMIM. |
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| Intellectual disability - microarray and sequencing v4.68 | CHAMP1 | Achchuthan Shanmugasundram Phenotypes for gene: CHAMP1 were changed from Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 to Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.68 | CHAMP1 | Achchuthan Shanmugasundram Phenotypes for gene: CHAMP1 were changed from Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 to Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.68 | CHAMP1 | Achchuthan Shanmugasundram Phenotypes for gene: CHAMP1 were changed from Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 to Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.68 | CHAMP1 | Achchuthan Shanmugasundram Phenotypes for gene: CHAMP1 were changed from Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 to Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.67 | CHAMP1 | Achchuthan Shanmugasundram Phenotypes for gene: CHAMP1 were changed from Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 to Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.67 | CHAMP1 | Achchuthan Shanmugasundram Phenotypes for gene: CHAMP1 were changed from Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 to Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.67 | CHAMP1 | Achchuthan Shanmugasundram Phenotypes for gene: CHAMP1 were changed from INTELLECTUAL DISABILITY to Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.46 | BAP1 | Mafalda Gomes commented on gene: BAP1: Kry et al. (2022) performed trio-WES in a cohort with a rare syndromic NDD and identified de novo missense variants in 11 unrelated individuals. All individuals had DD or ID characterised notably by speech (11/11) and motor delay (6/11). Additional common characteristics were hypotonia, (7/11), seizures (6/11), and abnormal behaviour (8/10), including ASD, ADHD, and hypersensitivity. Almost all individuals showed dysmorphic facial features (10/11), and more than half (6/11) had skeletal malformations involving the hands, feet, or spine. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In summary, this gene should be promoted to GREEN in this panel, with autosomal dominant mode of inheritance. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1771 | FBXW7 | Arina Puzriakova Phenotypes for gene: FBXW7 were changed from Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate to Developmental delay, hypotonia, and impaired language, OMIM:620012 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1764 | ARFGEF1 | Eleanor Williams Phenotypes for gene: ARFGEF1 were changed from Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027 to Intellectual disability, MONDO:0001071; Epilepsy, MONDO:0005027; Developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, OMIM:619964 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1748 | ACOX1 | Arina Puzriakova Added comment: Comment on mode of inheritance: Adding 'watchlist_moi' tag to monitor for evidence supporting association of monoallelic variants in this gene with ID. To date, three unrelated cases have been reported (PMID: 32169171) with dominant variants. Two patients had impaired cognition while one remained cognitively intact. These cases should be picked up via other routes (neuropathy, hearing loss) but monitoring evidence pertaining to monoallelic variants may be of value. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1746 | BAP1 |
Rachel Challis gene: BAP1 was added gene: BAP1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: BAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BAP1 were set to 35051358 Phenotypes for gene: BAP1 were set to Intellectual disability; short stature; autism spectrum disorder Review for gene: BAP1 was set to GREEN gene: BAP1 was marked as current diagnostic Added comment: 11 de novo BAP1 missense variants identified predominantly in UCH domain. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. Analysis of blood from affected patients demonstrated impaired H2A deubiquitination compared to controls. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1720 | PTPA |
Konstantinos Varvagiannis gene: PTPA was added gene: PTPA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PTPA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPA were set to 36073231 Phenotypes for gene: PTPA were set to Intellectual disability; Parkinsonism Penetrance for gene: PTPA were set to Complete Review for gene: PTPA was set to AMBER Added comment: Biallelic PTPA pathogenic variants lead to a form of ID with later-onset parkinsonism based on 4 individuals from 2 families in the literature. Affected individuals were homozygous for missense variants demonstrated to result to reduced mRNA and protein levels as well as PP2A complex activation. Drosophila studies support an age-dependent locomotor dysfunction. Variants in other PP2A-complex-related genes also lead to NDDs. Summary provided below. There is currently no associated phenotype in OMIM, G2P, PanelApp Australia or SysNDD. Consider inclusion in relevant panels (ID, Parkinsonism/movement disorders, etc) with amber rating pending further reports. ------ Fevga, Tesson et al (2022 - PMID: 36073231) describe the features of 4 individuals, from 2 unrelated families, with biallelic pathogenic PTPA variants. These presented with normal or delayed early milestones, learning disability and ID (mild to moderate) followed by progressive signs of parkinsonism (at the age of 11 yrs in 2 sibs, 15 yrs in another individual). Motor symptoms were responsive to levodopa and later to deep brain stimulation. Linkage analysis in one consanguineous family followed by exome revealed homozygosity for a missense PTPA variant (NM_178001:c.893T>G/p.Met298Arg). Exome sequencing in affected subjects from the 2nd family revealed homozygosity for a further missense variant (c.512C>A/p.Ala171Asp). There were no other candidate variants for the phenotype following parental / segregation studies. Role of the gene: As the authors discuss, PTPA (or PPP2R4) is ubiquitously expressed in all tissues incl. brain and encodes a phosphotyrosyl phosphatase activator of the dimeric form of protein phosphatase-2A (PP2A). PP2A in turn, is the major Ser/Thr phosphatase in brain targeting a large number of proteins involved in diverse functions. Activation of PP2A is dependent on its methylation, which is negatively regulated by the PP2A-specific methylesterase (PME-1). By binding to PME-1, PTPA counteracts the negative influence of the former on PP2A. Pathogenic variants in genes encoding subunits/regulators of the PP2A complex (e.g. PPP2R1A or PPP2CA) are associated with neurodevelopmental disorders. Variant studies: Upon overexpression of wt and both variants in a HEK-293 cell line the authors demonstrated that both variants resulted in significantly reduced mRNA and protein levels (which for Ala171Asp were attributed to increased proteasomal degradation). Both variants were shown to result in impaired PP2A complex activation compared to wt. Drosophila / animal models: Pan-neuronal RNAi-mediated knockdown of ptpa in Drosophila resulted in an age-dependent locomotor dysfunction, reversible with L-DOPA treatment. Previous studies in mice suggest cognitive/electrophysiological impairments upon downregulation of PP2A activity in transgenic mice. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1701 | UBAP2L |
Konstantinos Varvagiannis gene: UBAP2L was added gene: UBAP2L was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: UBAP2L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: UBAP2L were set to 35977029 Phenotypes for gene: UBAP2L were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Seizures; Microcephaly; Abnormality of head or neck; Short stature; Abnormality of the skeletal system Penetrance for gene: UBAP2L were set to unknown Review for gene: UBAP2L was set to GREEN Added comment: Based on Jia et al (2022 - PMID: 35977029) speech, motor delay as well as ID are observed in individuals harboring de novo pLoF variants in UBAP2L. The gene encodes a regulator of the stress granule (SG) assembly. Extensive evidence is provided on the effect of variants as well as the role of UBAP2L and other genes for components and/or regulation of SG in pathogenesis of NDDs. Among others a Ubap2l htz deletion mouse model (behavioral and cognitive impairment, abnormal cortical development due to impaired SG assembly, etc). Data from 26 previous studies, aggregating 40,853 probands with NDDs (mostly DD/ID, also ASD) suggest enrichment for DNMs in UBAP2L or other genes previously known and further shown to be important for SG formation (incl. G3BP1/G3BP2, CAPRIN1). Details provided below. Not associated with any phenotype in OMIM, G2P or SysNDD. -------- Jia et al (2022 - PMID: 35977029) describe 12 affected individuals with heterozygous de novo pLoF variants in UBAP2L. Phenotype: Features included hypotonia, speech (11/11) and motor delay (8/12), ID (8/10 with formal evaluation), variable behavioral concerns (ADHD 5/11, ASD in 4/10, etc). Seizures were reported in 7/12 with 3/10 having a formal diagnosis of epilepsy. Few had microcephaly (3/10). Facial dysmorphisms were common (9/9) and included abnormal palpebral fissures, deep prominent concha, high broad forehead, hypertelorism, thin upper lip and mild synophrys (each in 4 or less individuals). Short stature or skeletal alterations were described in some (4/10 each). Role of the gene: UBAP2L encodes an essential regulator of stress granule assembly. Stress granules are membraneless cytoplasmic compartments in eukaryotic cells, induced upon a variety of stressors and playing a role in regulation of gene expression. Variants identified : 9 nonsense/frameshift UBAP2L variants and 3 splicing ones were reported, in all cases as de novo events, upon trio/quad exome sequencing. All were absent from gnomAD. There were no other causative variants. Variant effect/studies (NM_014847.4 / NP_055662.3) : - Minigene assays revealed that the 3 splice variants all resulted in out-of-frame exon skipping. - In patient fibroblasts one of these splice variants was demonstrated to result to reduced protein levels. - 8 of the 9 nonsense/frameshift variants were predicted to result to NMD. - 1 nonsense variant (c.88C>T/p.Q30*) was shown to result to decreased protein expression in patient fibroblasts, with detection of the protein using an antibody for the C terminus but not the N terminus. Protein N-terminal sequencing confirmed that the protein lacked the N terminus, with utilization of an alternative start site (11 codons downstream). - Generation of HeLa UBAP2L KO cell lines resulted in significant reduction of SG numbers which was also the case for 4 variants studied, under stress conditions. - The protein has a DUF domain (aa 495-526) known to mediate interaction of UBAP2L with G3BP1 (a stress granule marker) with deletions of this domain leading to shuttling of UBAP2L from the cytoplasm to the nucleus. Truncating variants upstream of the DUF domain were shown to result in nuclear localization. Mouse model : - The authors generated Ubap2l KO model with hmz deletion of Ubap2l resulting in a lethal phenotype (2.6% survived) and htz deletion leading to behavioral issues (low preference for social novelty, anxious-like behaviors) and cognitive impairment. - Ubap2l haploinsufficiency resulted in abnormal cortical development and lamination with reduction of neural progenitor proliferation. - Ubap2l deficiency was shown to impair SG assembly during cortical development both under physiological stress conditions or upon utilization of an oxidative stress inducer. Additional evidence of UBAP2L and SG overall in pathogenesis of NDDs: - Based on DNMs from 40,853 individuals with NDDs from 26 studies (9,228 with ASD, 31,625 with DD/ID) the authors demonstrate significant excess of DNM in 31 genes encoding SG components, regulators or both, the latter being the case for UBAP2L and 2 further genes (G3BP1 and G3BP2 - both with crucial roles in SG assembly). - Excess dn splice-site (N=3) and missense (N=5) variants in G3BP1 were observed in the above cohort [c.95+1G>A, c.353+1G>T, c.539+1G>A / p.S208C, R320C, V366M]. - Excess dn missense (N=7) variants in G3BP2 were observed in the above cohort [p.R13W, D151N, E158K, L209P, E399D, K408E, R438C]. - Generation of G3BP1 or G3BP2 KO HeLa cell lines and immunofluorescence upon use of oxidative stress inducer revealed significant reduction of stress granules. - Generation of HeLa cell lines for 5 G3BP1 mutants (R78C*, R132I*, S208C*, R320C*, V366M) and 7 G3BP2 mutants (p.R13W*, D151N*, E158K, L209P*, E399D, K408E, R438C) revealed that several (those in asterisk) resulted in significantly fewer SG formation under oxidative stress compared to WT while the subcellular distribution of the proteins under stress was identical to WT. - Among the identified genes for SG enriched for DNMs, CAPRIN1 was implicated in previous publications as a NDD risk gene with 3 dn missense SNVs reported (p.I373K, p.Q446H, p.L484P). CAPRIN1 binding to G3BP1/2 has been shown to promote SG formation. Significant reduction of SG was observed in CAPRIN1 KO HeLa lines. p.I373K abolished interaction with G3BP1/2 and disrupted SG formation. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1652 | MED13L | Arina Puzriakova Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1635 | PRDM13 |
Ivone Leong gene: PRDM13 was added gene: PRDM13 was added to Intellectual disability. Sources: Expert Review Amber,Literature Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRDM13 were set to 34730112 Phenotypes for gene: PRDM13 were set to congenital hypogonadotropic hypogonadism, MONDO:0015770; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761 |
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| Intellectual disability - microarray and sequencing v3.1606 | ATP6V0A1 |
Mike Spiller changed review comment from: Bott et al 2021 PMID: 34909687 17 individuals from 14 unrelated families 12 individuals with de novo variants in ATP6V0A1. Associated with severe intellectual disability and refractory seizures following initial normal development. 1 stillborn; other 11 all have intellectual disability and slowing of developmental progression. 10 have epilepsy, microcephaly also common and MRI abnormalities in some. Dysmorphic features less common. 7/12 have recurrent hotspot variant NM_001130021.3 c.2219G>A R740Q. Biallelic inheritance also suggested - 2 separate families (apparently unrelated by IBD analysis) with affected individuals compound heterozygous for c.445delG p.(Glu149fs) and c.1483C>T p.(Arg495Trp). Phenotype of ID, epilepsy, but with ataxia and cerebellar anomalies. Gene involved in proton transport into organelles. Cell lines stably expressing R740Q show reduced endolysosome acidification consistent with reduced transporter function. Supported by data showing impaired maturation of Cathepsin D (requires acidic pH). Also refer to studies of yeast homologue showing that R735 (corresponds to human R740) is essential for proton transport function (Kawasaki-Nishi et al 2001 PMID: 11592980). Strong evidence that pathogenic missense variants in this gene cause severe ID/epilepsy, Less certain for biallelic inheritance. Recommend upgrade to Green for ID and epilepsy.; to: Bott et al 2021 PMID: 34909687 17 individuals from 14 unrelated families 12 individuals with de novo variants in ATP6V0A1. Associated with severe intellectual disability and refractory seizures following initial normal development. 1 stillborn; other 11 all have intellectual disability and slowing of developmental progression. 10 have epilepsy, microcephaly also common and MRI abnormalities in some. Dysmorphic features less common. 7/12 have recurrent hotspot variant NM_001130021.3 c.2219G>A R740Q. Biallelic inheritance also suggested - 2 separate families (apparently unrelated by IBD analysis) with affected individuals compound heterozygous for c.445delG p.(Glu149fs) and c.1483C>T p.(Arg495Trp). Phenotype of ID, epilepsy, but with ataxia and cerebellar anomalies. Gene involved in proton transport into organelles. Cell lines stably expressing R740Q show reduced endolysosome acidification consistent with reduced transporter function. Supported by data showing impaired maturation of Cathepsin D (requires acidic pH). Also refer to studies of yeast homologue showing that R735 (corresponds to human R740) is essential for proton transport function (Kawasaki-Nishi et al 2001 PMID: 11592980). Strong evidence that heterozygous pathogenic missense variants in this gene cause severe ID/epilepsy, Less certain for biallelic inheritance. Recommend upgrade to Green for ID and epilepsy. |
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| Intellectual disability - microarray and sequencing v3.1562 | PABPC1 |
Konstantinos Varvagiannis gene: PABPC1 was added gene: PABPC1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PABPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PABPC1 were set to 35511136 Phenotypes for gene: PABPC1 were set to Global developmental delay; Expressive language delay; Intellectual disability; Behavioral abnormality; Seizures Penetrance for gene: PABPC1 were set to unknown Review for gene: PABPC1 was set to AMBER Added comment: Wegler et al (2022 - PMID: 35511136) describe the phenotype of 4 individuals with de novo variants in the PABP domain of PABPC1. Overlapping features included DD (4/4) with weak expressive language (4/4), learning disability/borderline intellectual functioning (in 2) to more severe ID (in 2 others), treatable/self-limiting seizures (in 3 for whom this information was available) as well as variable behavioral issues (impaired social skills, concentration/sleeping problems, ADHD, anxiety or autism). Other features involved feeding difficulties (3/4), hearing impairment (in 2/3) or variable other phenotypes. Contribution of de novo variants found in other genes was thought possible. All 4 were investigated by trio exome sequencing following negative previous routine diagnostic work-up. WES revealed heterozygous de novo PABPC1 variants, 3 of which were missense SNVs (c.1687G>A/p.Gly563Ser, c.1691A>C/p.Glu564Gly, c.1709T>C/p.Ile570Thr using NM_002568.3) and a fourth an in-frame deletion (c.1664_1666del/p.Pro555del). Additional de novo variants were reported in 3 cases (IGF2R missense SNV, htz KDM5B stopgain, RBBP4 - the latter not associated with any phenotype to date). PABPC1 encodes Polyadenylate-binding protein, cytoplasmic, 1 which as the authors summarize has an important role overall in regulation of gene expression (poly(A) tail length, mRNA formation, export of processed mRNAs to cytoplasm, translation initiation promotion and termination, mRNA stability, NMD). Translation is regulated by Polyadenylate-binding protein–interacting proteins (PAIPs) which control PABP activity. PAIP2 in particular, which is highly expressed in CNS, is known to inhibit translation via binding to the PABP domain of PABPC1 and is thought to play an important role through transcriptional regulation for synaptic plasticity and memory. To evaluate plausibility as a DD gene the authors performed analyses using publicly available data, with PABPC1 ranking high in terms of protein-protein interaction (PPI) and co-expression with known DD genes. Variants were absent from gnomAD with in silico predictions in favour of a deleterious effect. While PABPC1 is intolerant to both missense and LoF variants (z-score 4.49, pLI of 1), occurrence of these 4 dn variants and their clustering in the PABP domain appeared to be of statistical significance (p=0.002 and p=2.8x10-8) rather than being explained by random occurrence. Structural modeling of variants suggested that all were in close spatial vicinity within the PABP domain, likely influencing PAIP2 binding. In HeLa cells the variants were shown not to affect subcellular localization (to the cytoplasm) compared to wt. In addition, there were no significant differences upon stress conditions under which the protein localizes to stress granules. In HeLa cells, co-immunoprecipitation assays using C-terminal HA tagged PABPC1, revealed that 3 variants (Gly563Ser, Glu564Gly, Ile570Thr) significantly reduced physical PABPC1-PAIP2 interaction compared with wt, which was also observed though to a not significant extent for Pro555del. (Other variants from literature also studied as discussed below). Pabpc1 is highly expressed in all regions of the developing mouse brain with remarkable decrease after birth, suggesting a critical role in prenatal brain development. Through electroporation with Pabpc1-directed shRNA the authors provided evidence that Pabpc1 LoF results in abnormal neural progenitor cell proliferation with rescue experiments using human WT or missense variants (Gly563Ser, Glu564Gly, Ile570Thr) showing that only the WT could rescue the proliferation phenotype. Overall a model whereby weakened PABPC1-PAIP2 interaction, leading to dysregulation to gene expression homeostasis and interference with proliferation of neural progenitors and the later to the NDD phenotype is proposed. Given previous reports in the literature for de novo PABPC1 variants, namely Lys138Glu, Asp204Val, Arg481His, Pro456Leu the authors noted that the phenotypes reported in the respective individuals were rather explained by other variants (16p11.2 dup, ARID1A dn, TBL1XR1 dn variants). These PABPC1 variants do not lie in the PABP domain, have lower in silico pathogenicity scores (MPC/CADD), with structural modelling suggestive of no significant effect. Importantly, upon co-immunoprecipitation studies with PAIP2 which were here performed, these variants had no effect. Pathogenicity of these variants - not located within the PABP domain - through another mechanism cannot be however ruled out. (PMIDs cited, though not reviewed based on this discussion: De Rubeis et al, 2014 - PMID: 25363760, Guo et al, 2019 - PMID: 30504930, Kaplanis et al, 2020 - PMID: 33057194). Currently there is no PABPC1-related phenotype in other databases (incl. OMIM, G2P, SysID, PanelApp Australia). Consider inclusion in the gene panels for ID and epilepsy with amber / green rating (DD with or without ID in >= 3 individuals/families/variants – also the case for seizures, role of the gene, statistical evidence for the gene/occurrence and clustering of variants, functional studies with strong evidence for at least 3 variants || learning difficulties/borderline intellectual functioning in 2 affected individuals, phenotype in few might be "blended" due to additional de novo variants). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1562 | GNAI1 | Arina Puzriakova Phenotypes for gene: GNAI1 were changed from GNAI1 syndrome to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, OMIM:619854 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1556 | FBXW7 |
Konstantinos Varvagiannis gene: FBXW7 was added gene: FBXW7 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FBXW7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FBXW7 were set to 33057194; 35395208; 30885698; 26482194; 19963109; 20332316 Phenotypes for gene: FBXW7 were set to Neurodevelopmental abnormality; Global developmental delay; Intellectual disability; Macrocephaly; Microcephaly; Abnormality of brain morphology; Abnormality of the corpus callosum; Abnormality of the cerebellum; Abnormality of the cardiovascular system; Seizures; Strabismus; Abnormality of the palate Penetrance for gene: FBXW7 were set to unknown Review for gene: FBXW7 was set to AMBER Added comment: While Kaplanis et al (2020 - Ref1), identified FBXW7 among 285 genes significantly associated with developmental disorders, a recent study by Stephenson et al (2022 - Ref2) describes the neurodevelopmental phenotype of 35 individuals making this gene relevant to the current panel. There are previous reports of dn/inh germline variants in individuals (likely 7) with tumor predisposition although a neurodevelopmental phenotype was not reported in most cases. There is currently no FBXW7-related phenotype in OMIM. The gene is included in the DD panel of G2P [associated with: FBXW7-related developmental disorder (monoallelic), confidence: definitive, citing the study by Kaplanis et al]. SysID lists FBXW7 among the candidate ID genes (same Ref.). The gene has a green rating for ID in PanelApp Australia (VCGS participating in the recent publication). Consider inclusion with amber/green rating. Also consider inclusion in other panels that may be relevant(macro/microcephaly, seizures, CHD, corpus callosum / cerebellar abnormalities, cleft palate, WT, etc). [1]------------ Kaplanis et al (2020 - PMID: 33057194), by combining exome data from 31,058 parent offspring trios from the DDD study, Radboudumc and GeneDx, identified 285 genes significantly associated with developmental disorders, 28 of which (incl. FBXW7) not previously robustly associated with these disorders. [2]------------ Stephenson et al (2022 - PMID: 35395208) provide clinical information on 35 individuals harboring germline monoallelic FBXW7 variants or chromosomal deletions spanning this gene. The phenotype corresponded to a phenotypically variable NDD characterized by hypotonia (in about 2/3), neurodevelopmental abnormality (34/35 - as discussed later), seizures (8/35), abnormal brain morphology (13/17 - in 7/17 abnormal CC, in 5/17 abn. cerebellum, etc), head circumference (macrocephaly in 10/35, microcephaly in 2/35). Additional features included abnormal palate or uvula morphology (10/35 - cleft palate in 3 from 2 families while 1 individual from a 3rd family had bifid uvula) or abnormal heart morphology (11/35), ophthalmologic features (e.g. strabismus in 5/35) or hearing impairment (2/35). There was no recognizable gestalt (deeply set eyes with upper eyelid fullness in 9/35). As for the DD/ID this ranged from borderline to severe, characterized as mild-moderate in 27/35, severe in 3/35. One individual did not present neurodevelopmental abnormality 1/35. FBXW7 encodes F-box and WD40 domain protein 7 which is part of the SCF E3 ligase complex (SKP1/CUL1/F-box protein) exerting a role of recognition and binding of target proteins for degradation by the ubiquitin proteasome system. In this way FBWX7 participates in regulating a network of proteins involved in cell division, growth, differentiation (as summarized by Roversi et al - Ref2). Most individuals were investigated by trio-WES/WGS (few with singleton WES or CMA only). 28 germline FBXW7 variants were identified incl. missense (N=21), pLoF (predicted or not to undergo NMD) and 2 deletions encompassing but not limited to FBXW7. Additional SNVs/CNVs (e.g. an inh intragenic DPP6 dup in one individual (#9) with deletion, other de novo 4q CNVs (#10), an inh 22q spanning partially an ISCA TS region, a CACNA1A and KMT2D SNV, etc) were reported in few individuals. Most variants arose dn (N=30) with two individuals displaying mosaicism (2/30) and three individuals having inherited the variant from their affected parent. CNVs had occurred dn. 3 missense SNVs were recurrent in unrelated individuals. All variants identified affected all FBXW7 isoforms. As the authors comment missense variants clustered at the C-terminal half of the protein with most (16/21) occurring within the WD40 domain. [The N-terminal part commented in the literature to affect localization]. The crystal structure of FBXW7 and SKP1 complex has been determined with CYCLIN E1/DISC1 as substrates, and in silico modeling revealed that all missense variants aligned with residues required for this interaction, or adjacent ones. All were absent from gnomAD, while missense variants from gnomAD (N=78) were not predicted have significant effect on the binding affinity. Variant studies revealed that most missense variants (6/7 tested - Arg689Gln being the exception) are unlikely to cause protein instability or degradation in vivo. Co-expression of these missense variants with CYCLIN E1 / E2, known FBXW7 substrates revealed that variants were less efficient at degrading the substrate with variants in the WD40 domain having greater impact (in some cases E1 / E2 - specific). Elav-Gal4 mediated neuronal knockdown of the Drosophila ortholog archipelago (ago) using 2 RNAi-s with different efficiency was shown to affect learning or compromise neuronal function (also related to the level of knockdown). The authors summarize results from animal models for the role of this gene in development and the nervous system. KO mice die in utero at E10.5 manifesting abn. of hematopoietic or vascular development and heart-chamber maturation(*). Some htz knock-in for human cancer variants, display perinatal lethality, abn lung, cleft palate (30%)(*),etc. Conditional gut specific deletion results in impaired differentiation of intestinal goblet cells (*)(constipation in 16/35 in cohort). KO limited to CNS and PNS results in defective sucking and morphological brain abnormalities. Haploinsufficiency in the nervous system was associated with impaired differentiation of neural stem cells (possibly through a Notch-mediated mechanism). KO in Schwann cells of the peripheral nervous system resulted in enhanced myelination. Excessive oligodendrocyte cells and hypermyelination (as a result of elevated Notch & mTOR signaling) are observed in homozygous mutant zebrafish or after morpholino-mediated fbxw7 knockdown. Overall, the authors propose haploinsufficiency or loss-of-function as the underlying mechanism. Finally, as the authors comment, FBXW7 is a tumor suppressor among the most commonly mutated genes in human cancer (3.5%). Germline variants have been previously reported in individuals with cancer (Wilms tumor, rhabdoid, etc - most summarized below). However, none of the 35 individuals in this cohort (oldest 44 y.o.) had any history of cancer. Reports of individuals with germline variants causing (monoallelic) disruption of FBXW7 - cases without DD/ID: [3]------------ Mahamdallie et al (2019 - PMID: 30885698) investigated with WES a cohort of 890 individuals with Wilms tumor (799 non-familial disease, 91 from WT pedigrees). In this context they identified 4 individuals having developed WT (ages: 28-76m) with FBXW7 dn or inherited LoF variants (710G>A / p.Trp237* dn - 1972C>T / p.Arg658* - inh:NA, 1017_1021del5, 670C>T - paternal / p.Arg224* inh:NA - RefSeq not provided). One additional individual with a missense variant (1753A>T / p.Ser585Cys - dn) had developed rhabdoid tumor. While the authors mentioned additional features for other subjects in their cohort, among the 5 individuals with FBXW7 variants, only one had hypotonia (ID_0592) and another (ID_7520) had two febrile convulsions. [4]------------ Roversi et al (2015 - PMID: 26482194) described the phenotype of a 34 y.o. female with syndromic presentation (macrocephaly, nephrotic syndrome due to FSGS, Hodgkin's lymphoma, Wilms tumor, ovarian cystadenoma, breast carcinoma) harboring a 157 kb deletion of 4q31.3. Eventual DD/ID was not reported despite detailed clinical description. The deletion spanned almost the entire FBXW7 gene and a pseudogene (hg19 - chr4:153205202-153362047). The authors provided evidence that the del affected the maternal allele as dn event (maternal mosaicism excluded). Expression of FBXW7 in patient-derived EBV lymphoblastoid cell line revealed decreased levels of expression compared to controls. At somatic level, the authors looked for eventual 2nd hit in tumor tissue (which was not the case) while they demonstrated decreased FBXW7 expression in a WT sample compared to normal renal tissue. Previously, variants in other genes candidate for the phenotype were ruled out (Sanger & MLPA for TP53, BRCA1/2, PALB2, WT1, 11p15 MS-MLPA, std karyotype). [5]------------ Kuiper et al (2015 - PMID: 19963109), in a 58 y.o. patient with recurrence of RCC, identified a constitutional translocation [t(3;4)(q21;q31)]. Using long-range PCR they defined the breakpoints at 3q21.3 (128379059 - hg18) between the PLXNA1 and C3orf56 genes while the chr4 breakpoint was located within the second intron of FBXW7 (pos. 153500813 - hg18). There were no additional phenotypes reported. [6]------------ Williams et al (2010 - PMID: 20332316) reported a patient with WT harboring germline variants in WT1 and FBXW7. While the phenotype was sufficiently explained by a germline stopgain WT1 variant with a frameshift WT1 variant (as 2nd hit) confined to the tumor, the authors identified a germline in-frame FBXW7 insertion in the same individual (c.45_46insCCT / p.Thr15_Gly16insPro - RefS : NA) [if correct corresponding to: https://gnomad.broadinstitute.org/variant/4-153332910-C-CAGG - 345/281696 alleles in gnomAD]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1544 | DTYMK |
Konstantinos Varvagiannis gene: DTYMK was added gene: DTYMK was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DTYMK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DTYMK were set to Global developmental delay; Intellectual disability; Microcephaly; Seizures; Global brain atrophy; Cardiorespiratory arrest Phenotypes for gene: DTYMK were set to 31271740; 34918187; 35346037 Penetrance for gene: DTYMK were set to Complete Review for gene: DTYMK was set to GREEN Added comment: 4 individuals (from 3 families) harboring biallelic DTYMK pathogenic variants have been reported. Consider inclusion in the current panel with green rating given consistent and relevant phenotype and evidence provided to date [effect of variants (LoF), pathogenesis, similar phenotypes in zebrafish model, etc]. Relevant studies are summarized below. ---- Lam et al (2019 - PMID: 31271740) described two siblings aged 25m and 7y, harboring biallelic DTYMK variants. The phenotype consisted of hypotonia, congenital microcephaly, DD, severe ID. Other shared features included raised serum lactate, pyruvate and alanine. The phenotype was more pronounced in the younger one (epilepticus during febrile illness, epilepsy on multiple anti-convulsants, evidence of regression, etc). Brain MRI revealed marked cerebral atrophy among the findings while a lactate peak was present in spectroscopy. The elder brother developed an episode of sudden onset coma with respiratory failure at the age of 7y. Quartet WES identified compound heterozygosity for a fs and a missense DTYMK variant (NM_012145.3:c.287_320del / p.Asp96Valfs*8 - c.295G>A / p.Ala99Thr). There were no additional findings. Previous genetic panel analysis for epilepsy was unremarkable for the 1st sib. There are two pathways for synthesis of dNTPs, the de novo pathway operating in the cytosol only and the salvage operating in both cytosol and mitochondria. DTYMK encodes (deoxy)thymidylate kinase which catalyzes conversion (phosphorylation) of dTMP to dTDP - a step right after convergence of both pathways - in the dTTP synthesis pathway. Mutations in TK2, an enzyme phosphorylating thymidine in mitochondria to dTMP have been associated with mitochondrial DNA depletion syndrome (MDDS). Given this and as the 2 sibs had raised serum lactate and pyruvate, the authors performed in silico analyses to calculate mtDNA/nDNA ratio dividing the respective read depths for mitochondrial and nuclear DNA obtained from WGS data of the two sibs (blood). This ratio was shown to be reduced in the more severely affected sib (65.5% of control) although this was not the case for the mildly affected brother (114.6%). As a control a non-MDDS mitochondrial cytopathy sample (corresponding to m.8993T>G) was used. The respective ratio which was calculated for a known POLG-related MDDS case was 15.6%. ---- Vanoevelen et al (2022 - PMID: 34918187) describe two unrelated children with hypotonia, absence of developmental progress, microcephaly, seizures (recurrent febrile seizures/myoclonic jerks). Severe cerebral atrophy (with unaffected cerebellum) was observed upon brain imaging. Other findings included puffy body/extremities. Both had complications following respiratory illness leading to demise. CNS pathology in the 1st individual revealed massive neuronal dropout, with sparing of dentate nucleus and brainstem. CMA in both cases was normal. This was also the case for extensive metabolic investigations (which provided no evidence of eventual mitochondrial dysfunction). WES revealed compound heterozygosity for 2 missense variants in the first individual (NM_012145.3:c.382G>A - p.Asp128Asn and c.242C>T - p.Pro81Leu). The second individual, born to consanguineous parents, was homozygous for c.242C>T / p.Pro81Leu. In silico predictions varied although each variant were (mostly) suggestive of a deleterious effect. Variants were both ultrarare without homozygotes in ExAC,. The authors generated a dtymk ko zebrafish model (hmz for a frameshift variant). Zebrafish exhibited markedly smaller eyes and pericardiac edema (3dpf-), twitching movements somewhat reminiscent of epilepsy (at 3dpf), prominent edema of brain and intestine. Head size was significantly smaller at a timepoint prior to brain edema (also after correction for length). Histology provided evidence of empty spaces in brain, suggestive of neurodegeneration, with high amounts of apoptotic cells. dTMPK activity was measured in zebrafish (at 5dpf) as well as in fibroblasts from one individual and in both cases, it was barely detectable and significantly lower compared to wt/htz zebrafish or to the activity in fibroblasts from the parents of the individual tested. In fibroblasts from the same individual with comparison to his parents, the authors demonstrated that DNA replication was impaired (using pulse-EdU staining to quantify cells in S-phase). Assessment of cell proliferation in the brain of dtymk ko zebrafish using phospo-Ser10-Histone H3 (pH3) staining was suggestive of severe proliferation defects in forebrain. Impaired biosynthesis of nucleotides for DNA synthesis/repair would be predicted to result in nucleotide pool imbalance, leading to incorporation of ribonucleotides in genomic DNA with - in turn - impairment of DNA replication and genomic instability (sensitivity to strand breakage). In line with this, genomic DNA of ko zebrafish following alkaline hydrolysis and alkaline gel electrophoresis was shown to migrate at lower position and to be more fragmented indicating increased sensitivity (due to incorporation of ribonucleotides). Visualization of DNA breakage by γH2AX staining, following UV-irradiation of zebrafish embryos revealed persistence of elevated γH2AX levels and DNA damage response signaling, interpreted as increase in unrepaired DNA breaks. mtDNA copy numbers in fibroblasts from the affected individual was somewhat but not significantly lower compared to his parents. Importantly, the copy numbers were similar to controls (N=5) which overall does not support mtDNA depletion as a consequence of DTYMK deficiency. Integrity of mtDNA did not appear to be compromised , with the mitochondrial genome migrating at the expected length of 16,5 kb with no indications of mtDNA deletions for both affected individual and his parents. Activity of the mitochondrial respiratory complexes I-V in fibroblasts from the affected individual was comparable to that of his parents. Overall, there was no evidence for mtDNA depletion (although not studied in muscle biopsy) while functional studies failed to demonstrate mitochondrial dysfunction. The authors discuss other disorders of impaired dTTP metabolism due to mutations in TYMP, RRM2B or CAD. ------ In a recent study using zebrafish model, Hu Frisk et al (2022 - PMID: 35346037) further demonstrate that Dtymk is essential for neurodevelopment providing evidence for expression of a compensatory thymidylate kinase-like enzyme at later stages of development (explaining survival of ko dtymk zebrafish despite the central role of this enzyme in dTTP generation). [Not further reviewed] Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1530 | MAN2C1 |
Konstantinos Varvagiannis gene: MAN2C1 was added gene: MAN2C1 was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: MAN2C1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAN2C1 were set to 35045343 Phenotypes for gene: MAN2C1 were set to Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Abnormality of the corpus callosum; Ventriculomegaly; Polymicrogyria; Abnormality of the face; Macrocephaly Penetrance for gene: MAN2C1 were set to unknown Review for gene: MAN2C1 was set to GREEN Added comment: Biallelic pathogenic MAN2C1 variants cause Congenital disorder of deglycosylation 2 (# 619775). Mild to moderate impairment of intellectual development is a feature in most patients as in the OMIM's clinical synopsis for this disorder. ---- Specifically, Maia et al (2022 - PMID: 35045343) report the clinical features based of 6 relevant individuals (4/6 aged 4-18years and 2/6 fetuses) from 4 families. These individuals had non-specific dysmorphic features (micro/retrognathia being the most common in 5/6), different congenital anomalies, variable degrees of ID (3/4), as well as brain MRI abnormalities (PMG in 3/6 from 3 fam, ventriculomegaly in 3/6 from 2 fam, callosal anomalies in 4/6 from 3 fam, cerebellar hypoplasia 2/6 - 2 fam, vermis hypoplasia 4/6 - 3 fam etc). Macrocephaly was reported for 2/6 individuals (2 fam). While ID was observed in 3/4 individuals of relevant age (mild in 1/4, moderate in 1/4, unk in 1/4), delayed motor and language development was reported for all (4/4). All individuals harbored biallelic MAN2C1 variants following exome sequencing (previous investigations not reported), and Sanger sequencing was used for validation and segregation (parents/sibs). There were no putative pathogenic variants in known disease genes. MAN2C1 encodes mannosidase, alpha, class 2c, member 1, an enzyme playing a role in deglycosylation of free oligosaccharides (fOSs). The latter are generated and released in the cytoplasm or the ER lumen during N-glycosylation of proteins. fOSs are generated from two different pathways (ERAD and LLO) with a defect in an enzyme of the NGLY1 already described to cause a NDD due to defect of deglycosylation. In a later step oligossaccharides are trimmed by the action of ENGase to form fOS containing one GlcNAc (N-Acetylglucosamine) residue (fOSGn1) at the reducing end. Processing of these fOSs by the cytosolic α-mannosidase (MAN2C1) converts Man7-9Gn1 to Man5Gn1 subsequently transported to lysosomes for degradation. Variants incl. 3 missense SNVs incl. c.2612G>C/p.Cys871Ser, c.2303G>A/p.Arg768Gln, c.607G>A/p.Gly203Arg, one splice variant (c.601-2A>G/p.Gly201Profs*10) and one indel (c.2733_2734del/p.His911Glnfs*67). [RefSeq NM_006715.3] Most were present in gnomAD with low AF ranging from 0.013% to 0.11% while c.2303G>A/p.Arg768 has an AF of 0.33% with 5 homozygotes(*) in the database. Conservation and in silico predictions supported their effect. For the variant affecting the splicing acceptor site (c.601-2A>G) studies in patient fibroblasts confirmed skipping of ex6. Fibroblasts from 2 sibs cmp htz for Arg768Gln and c.601-2A>G (Gly201Profs*10) were studied for protein levels, demonstrating 90% reduction in the amount of MAN2C1. There was no truncated protein observed upon immunoblot. Protein abundance was not affected in fibroblasts from the individual who was homozygous for Gly203Arg. Mannosidase activities were studied upon overexpression in a HEK293 model, with Gly203Arg presenting similar activity to WT and Arg768Gln exhibiting only a tiny residual activity. Cys871Ser showed increased activity compared to WT. Using fibroblasts from controls and the same individuals as above, the authors showed that pathogenic MAN2C1 variants caused defects in fOS processing (delayed processing of high oligomannose species, reduced production of M5Gn1 with M8 and M9Gn1/2 species remaining at high levels) supporting a total/partial loss of mannosidase activity for Arg768Gln and Gly203Arg. In MAN2C1-KO HAP1 cell lines, M7-M9Gn1 species accumulated while M5Gn1 - the product of MAN2C1 - were absent. Complementation of KO HAP1 cells with Gly203Arg, Arg768Gln and Cys871Ser suggested impaired fOS processing for Gly203Arg and Arg768Gln (with significant amounts of M7-M9Gn1 species). Cells complemented with Cys871Ser did not exhibit fOS processing defects. The authors speculate that Cys871Ser could affect a non-mannosidase function of the enzyme relevant to brain development or that it might lead to abnormal inter-subunit interactions or tetramer formation. Finally, Maia et al summarize findings in previously described Man2c1-KO mice (cited PMID: 24550399). These appeared normal, did not exhibit differences in growth or lifespan and did not present behavioral alterations. Man2c1-KO mice had CNS involvement with histological analyses in favor of neuronal and glial degeneration with multiple vacuoles in deep neocortical layers and telencephalic white matter tracts. Vacuolization was not observed upon brain histology for the 2 fetuses studied which Maia et al speculate may occur at a later stage. In KO mice there was considerable accumulation of Man8–9GlcNAc oligosaccharides. ---- G2P includes MAN2C1 in it's DD panel (confidence: strong, MAN2C1-associated neurodevelopmental disorder with cerebral malformations). In PanelApp Australia, this gene is rated green in the ID, polymicrogyria, cerebellar hypoplasia and fetal anomalies gene panels. Consider inclusion in the current panel with green (3 individuals/families/variants, role of the gene, NDD phenotype also reported for NGLY1-related disorder of deglycosylation, variant studies) or amber rating (ID not a universal feature, still DD observed in all affected individuals). Please consider adding this gene in other relevant panels (as in PanelApp Australia, also for corpus callosum abnormalities, metabolic disorders, etc). Sources: Literature, Other |
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| Intellectual disability - microarray and sequencing v3.1529 | SLC38A3 |
Konstantinos Varvagiannis gene: SLC38A3 was added gene: SLC38A3 was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC38A3 were set to 34605855 Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia Penetrance for gene: SLC38A3 were set to Complete Review for gene: SLC38A3 was set to GREEN Added comment: Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284). The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7). Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations. In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families. Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam). The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs. SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle. While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability. Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7). Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways). Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457. There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels. Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered). Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc. Sources: Literature, Other |
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| Intellectual disability - microarray and sequencing v3.1520 | PAN2 |
Konstantinos Varvagiannis gene: PAN2 was added gene: PAN2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PAN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PAN2 were set to 29620724; https://doi.org/10.1038/s41431-022-01077-y Phenotypes for gene: PAN2 were set to Global developmental delay; Intellectual disability; Sensorineural hearing impairment; Abnormality of the genitourinary system; Abnormality of the cardiovascular system; Abnormality of blood and blood-forming tissues; EEG abnormality; Seizures; Anorectal anomaly; Abnormality of the skeletal system; Abnormality of the eye; Abnormality of head or neck Penetrance for gene: PAN2 were set to Complete Review for gene: PAN2 was set to AMBER Added comment: 1. Maddirevula et al (2018 - PMID: 29620724) first reported on the phenotype associated with biallelic pathogenic variants in PAN2. This concerned a male (15DG2222) born to consanguineous parents and exhibiting MCA, dysmorphic features and global DD (age of 34 m). Features incl. imperforate anus, metopic craniosynostosis, scoliosis, CHD (PFO, PDA, VSD), renal anomalies (duplicated collecting system) and abnormalities of the eye (posterior embryotoxon, maculopathy). As the other 411 individuals from the cohort, the child had 1st-tier testing genetic testing using a dysmorphology/skeletal dysplasia panel of 296 genes. Subsequent autozygome analysis (Axiom genotyping platform) was used to identify ROH (authors state "segregating within the family", in pedigree the proband was the single affected person and single child). WES revealed a PAN2 indel. [NM_001166279.1:c.3162delC / p.(Ser1055Profs*4)]. There were no additional studies. Role of PAN2 and animal models discussed as below. --- 2. Reuter et al. (2022 - https://doi.org/10.1038/s41431-022-01077-y) describe the phenotype of 5 additional individuals - from 3 unrelated families (2 consanguineous) - harboring biallelic PAN2 variants. The authors review the phenotype of the previously described case. Features included DD (6/6), ID (4/5 with relevant age in the mild-moderate range, 1/5 had borderline IF), sensorineural hearing loss (5/6) and incompletely penetrant congenital anomalies of the heart (4/6 - TOF, septal defects, Ao root dilat), urinary malformations (4/6 - hypoplasia/agenesis, anovesical fistula), ophthalmological anomalies (2/6 - Rieger, posterior embryotoxon, etc). EEG anomalies or seizures were noted in 4/6. Craniofacial feat. in >=2/6 included cleft palate/bifid uvula, ptosis, hypertelorism, abn. of the nose, low-set ears, short neck. There was no comprehensive evaluation for skeletal dysplasia despite short stature/skeletal anomalies in multiple individuals. Hematological anomalies were reported in 2, possibly explained by another concurrent diagnosis (of GSD) in one individual. WGS was performed for 1 individual, and WES for 4 members of the 2nd family and the proband in the 3rd. ROH identified in all 3 families (1 non-consanguineous but from the same region of Italy) are mentioned in the suppl. Sanger sequencing for parents and affected/unaffected sibs was mentioned for the 2 families with solo WGS/WES. One individual had a dual - previously established - diagnosis (of SLC37A4-related GSD) not related to his NDD. There were no other candidate variants except for VUS or variants in 'genes of uncertain significance'. The majority of mammalian mature mRNAs have polyA tails, added during RNA processing. PAN2 encodes a subunit of the Pan2-Pan3 deadenylation complex which shortens mRNA 3' polyA tails, regulating mRNA stability/translation efficiency. Specifically Pan2 is the catalytic subunit, while the interaction with Pan3 mediates efficient mRNA binding. Deadenylation in cytoplasm is mostly carried out by the Pan2-Pan3 or Ccr4-Not compexes. While perturbations of mRNA metabolism/decay are established causes of NDD and ID. In particular, monoallelic variants in genes of Ccr4-Not complex (inc. CNOT1/2/3) already causative of NDDs. All affected individuals were homozygous for pLoF PAN2 variants, namely (NM_001166279.2): c.2335G>T / p.(Glu779*) [Fam1], c.3408dupT / p.(Glu1137*) [Fam2], c.574-2A>G / p.? [Fam3]. Variants were absent from gnomAD (where PAN2 has a pLI:0.94, o/e:0.19). There were no variant studies performed. The splicing variant is predicted in silico to abolish the splice-acceptor site, with in-frame skippling of ex5 which codes a repeat within the WD40 domain. Previous studies in yeast have shown that this domain is important for sensing the length of the polyA tail, with absence of this domain resulting in impaired deadenylation of 90A tails (similarly to complete Pan2 del) [cited PMID: 31104843]. Overall PAN2 loss-of-function is thought to be the underlying disease mechanism. Partial functional redundancy of Pan2/Pan3 (initiation of deadenylation) and Ccr4-Not complexes (further shortening of polyA) is speculated to mitigate consequences of PAN2 LoF in humans. In yeast Pan2Δ, Ccr4Δ and Pan2Δ/Ccr4Δ have been studied with more severe phenotypes in double mutants where ability to shorten mRNA polyA tails was abolished [cited PMID:11239395]. In yeast extracts lacking Pan2p and Pan3p, transcripts were polyadenylated to >90-200 adenosines [cited PMID: 9774670] Mouse mutants (MGI:1918984) had increased heart weight, increased eosinophil cell number while homozygosity for a stopgain allele (by ENU mutagenesis) was shown to result in embyonic lethality. Finally, given the presence of thrombocytopenia and anemia in 3 individuals (2 families) as well as the link between mRNA deadenylation and telomere disease, telomere length analyses from WGS data were performed (TelSeq/Expansion Hunter dn), but there was no evidence for telomeric shortening. --- Currently, there is no PAN2-related phenotype in OMIM/G2P/SysID/PanelApp Australia. --- Consider inclusion in the ID panel with amber rating [>3 individuals/families/variants, though variant studies not performed (NMD/splicing) and authors of 2nd study recognize possibility of additional/concurrent diagnoses in individuals from consanguineous families, possibility of missed dn variants due to singleton WGS/WES in 2 fam. Also the presumed deadenylation defect not studied to date]. Please consider adding this gene to other panels - eg. for sens. hearing loss (5/6 - 3 fam), urinary tract anomalies (4/6 - 4 fam), congenital (4/6 - 3fam), anorectal malformations (2/6 - 2 families, incl. fistula or imperforate anus), clefting (2/6 - 1 fam), hematological disorders, etc. For the time being, not added in epilepsy panel as some individuals had only EEG anomalies, few had also clinical seizures not necessarily requiring treatment. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1506 | PDZD8 |
Konstantinos Varvagiannis changed review comment from: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene. Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula. Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family. Previous genetic testing was not reported. Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above). The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES. Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B). Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz). Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon). PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided). The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood. The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology. Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia. Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports. Sources: Literature; to: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene. Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula. Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [*] (also to consider for MOI) : Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family. Previous genetic testing was not reported. Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above). The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES. Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B). Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz). Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon). PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided). The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood. The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology. Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia. Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1506 | PDZD8 |
Konstantinos Varvagiannis gene: PDZD8 was added gene: PDZD8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PDZD8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDZD8 were set to 35227461 Phenotypes for gene: PDZD8 were set to Global developmental delay; Intellectual disability; Autistic behavior; Behavioral abnormality; Myopathy; Abnormality of the face; Hypertelorism; Seizures; Disproportionate tall stature Penetrance for gene: PDZD8 were set to Complete Review for gene: PDZD8 was set to AMBER Added comment: Al-Amri et al (2022 - PMID: 35227461) describe 4 affected individuals, belonging to 2 independent consanguineous families, harboring biallelic pLoF PDZD8 variants. The phenotype corresponded to a syndromic form of ID with autistic features. Animal models provide additional evidence for a role of the gene. Details are provided concerning 3 affected sibs born to consanguineous parents (Fam-A) and a male proband born to first cousin parents (Fam-B) from different countries of the Arabian Peninsula. Features included DD (4/4), ID (4/4 - moderate to severe), autistic features[*](4/4), other behavioral problems (3/4 - 2 families). Variable facial features were observed (4/4 - incl. hypertelorism 4/4, myopathic face, open mouth, low-set ears, ptosis). 3 sibs presented with myopathy[*](3/4 overall - 1 fam - see below), and marfanoid habitus was observed in 2 (2/4 - 1 fam). 2 sibs had epilepsy (2/4 - from 1 family). 1 individual had congenital heart defect. [* -also to consider for MOI]Autistic features were however observed in a parent and a htz sib. Mild myopathy/reduced facial expression was also observed in both parents. Contribution of another variant - also within the region of shared homozygosity - to the phenotype of myopathy was deemed to be possible within this family. Previous genetic testing was not reported. Homozygosity mapping in the 1st family identified 3 homozygous regions (2.57 - 28 Mb) shared by all affected sibs. Singleton WES revealed 2 candidate variants within these regions, a PDZD8 frameshift variant [NM_173791.5:c.2197_2200del;p.(S733*)] lying in the last exon and an ANKRD2 missense one (discussed above). The proband in Fam-B was hmz for a nonsense variant in ex2 (of 5), namely c.894C>G/p.(Y298*) considered to be the most likely cause of his phenotype following singleton WES. Sanger sequencing was used for validation and segregation studies confirming carrier status of the parents and compatible results in unaffected sibs (tested : 2 in Fam-A, 3 in Fam-B). Both variants were absent from gnomAD (the first also from a pool of 50 control individuals of the same origin) where PDZD8 has a pLI of 1 (5 different pLoF variants, none hmz). Expression was not studied for the 2 variants. As a result, it is not known whether they escape NMD (as could be expected for the variant in the last exon). PDZD8 encodes an endoplasmatic reticulum (ER) transmembrane protein (TM). As the authors discuss, it has been previously shown that depletion of PDZD8 in neurons impairs endosomal homeostasis, decreases proximity of ER-mitochondria and decreases Ca+2 uptake mitochondria following synaptic transmission-induced release from the ER (sev. refs. provided). The gene is highly expressed in the human brain (incl. subclasses of GABAergic / glutamatergic neurons in adult primary motor cortex). The authors analyzed RNA-seq data from the BrainSpan project, demonstrating stable expression in human brain from 8 wks after conception to adulthood. The gene is not expressed in blood. The authors performed in vivo functional studies. Knockdown of the orthologous gene (CG10362) in Drosophila via RNA interference was shown to result in impairment of long-term memory. Mice homozygous for a variant introducing a premature termination codon exhibited restricted growth, brain structural alterations (incl. relative reduction of the CC, as in one subject), spontaneous stereotypies, decreased anxiety-like behavior with deficits in spatial memory and impaired hippocampal neurophysiology. Currently, there is no associated phenotype in OMIM, Gene2Phenotype, SysID or PanelApp Australia. Overall, this gene can be considered for inclusion in the ID panel probably with amber rating pending further reports. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1500 | CHKA |
Konstantinos Varvagiannis gene: CHKA was added gene: CHKA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CHKA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHKA were set to 35202461 Phenotypes for gene: CHKA were set to Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormality of movement; Abnormality of nervous system morphology; Short stature Penetrance for gene: CHKA were set to Complete Review for gene: CHKA was set to GREEN Added comment: Klöckner (2022 - PMID: 35202461) describe the phenotype of 6 individuals (from 5 unrelated families) harboring biallelic CHKA variants. Shared features incl. abnormal muscle tone(6/6 - hypertonia or hypotonia, 3/6 each), DD/ID (6/6,severe in 4, severe/profound in 2), epilepsy (6/6 - onset: infancy - 3y2m | epileptic spasms or GS at onset), microcephaly (6/6), movement disorders (3/6 - incl. dyskinesia, rigidity, choreoatetotic movements). 2/5 individuals exhibited MRI abnormalities, notably hypomyelination. Short stature was observed in 4/6. Eventual previous genetic testing was not discussed. Exome sequencing (quattro ES for 2 sibs, trio ES for 1 individual, singleton for 3 probands) revealed biallelic CHKA variants in all affected individuals. Sanger sequencing was performed for confirmation and segregation studies. Other variants (in suppl.) were not deemed to be causative for the neurodevelopmental phenotype. 3 different missense, 1 start-loss and 1 truncating variant were identified, namely (NM_0012772.2): - c.421C>T/p.(Arg141Trp) [3 hmz subjects from 2 consanguineous families], - c.580C>T/p.Pro194Ser [1 hmz individual born to consanguineous parents], - c.2T>C/p.(Met1?) [1 hmz individual born to related parents], - c.14dup/p.(Cys6Leufs*19) in trans with c.1021T>C/p.(Phe341Leu) in 1 individual. CHKA encodes choline kinase alpha, an enzyme catalyzing the first step of phospholipid synthesis in the Kennedy pathway. The pathway is involved in de novo synthesis of glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine being the most abundant in eukaryotic membranes. CHKA with its paralog (CHKB) phosphorylates either choline or ethanolamine to phosphocholine or phosphoethanolamine respectively with conversion of ATP to ADP. As the authors comment, biallelic pathogenic variants in CHKB cause a NDD with muscular dystrophy, hypotonia, ID, microcephaly and structural mitochondrial anomalies (MIM 602541). [Prominent mitochondrial patterning was observed in a single muscle biopsy available from an individual with biallelic CHKA variants]. Other disorders of the Kennedy pathway (due to biallelic PCYT2, SELENOI, PCYT1A variants) present with overlapping features incl. variable DD/ID (no-severe), microcephaly, seizures, visual impairment etc. CHKA variants were either absent or observed once in gnomAD, affected highly conserved AAs with multiple in silico predictions in favor of a deleterious effect. In silico modeling suggests structural effects for several of the missense variants (Arg141Trp, Pro194Ser presumably affect ADP binding, Phe341 lying close to the binding site of phosphocholine). Each of the missense variants was expressed in yeast cells and W. Blot suggested expression at the expected molecular weight at comparative levels. The 3 aforementioned variants exhibited reduced catalytic activity (20%, 15%, 50% respectively). NMD is thought to underly the deleterious effect of the frameshift one (not studied). The start-loss variant is expected to result in significantly impaired expression and protein function as eventual utilization of the next possible start codon - occurring at position 123 - would remove 26% of the protein. Chka(-/-) is embryonically lethal in mice, suggesting that complete loss is not compatible with life. Reduction of choline kinase activity by 30% in heterozygous mice did not appear to result in behavioral abnormalities although this was not studied in detail (PMID cited: 18029352). Finally, screening of 1566 mouse lines identified 198 genes whose disruption yields neuroanatomical phenotypes, Chka(+/-) mice being among these (PMID cited: 31371714). There is no associated phenotype in OMIM, Gene2Phenotype or SysID. Overall this gene can be considered for inclusion in the ID and epilepsy panes with green or amber rating (>3 individuals, >3 variants, variant studies, overlapping phenotype of disorders belonging to the same pathway, etc). Consider also inclusion in the microcephaly panel (where available this seemed to be of postnatal onset). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1451 | GLS | Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Developmental and epileptic encephalopathy 71, OMIM:618328; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1338 | PLXNA1 |
Zornitza Stark gene: PLXNA1 was added gene: PLXNA1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PLXNA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: PLXNA1 were set to 34054129 Phenotypes for gene: PLXNA1 were set to Neurodevelopmental disorder with cerebral and eye anomalies Review for gene: PLXNA1 was set to GREEN Added comment: Dworschak et al. (2021) via WES reported 10 patients from 7 families with biallelic (n=7) or de novo (n=3) PLXNA1 variants. Shared phenotypic features include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Seizures were predominantly reported in patients with monoallelic variants. Zebrafish studies showed an embryonic role of plxna1a in the development of the central nervous system and the eye. Biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1262 | CHRM1 |
Zornitza Stark gene: CHRM1 was added gene: CHRM1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CHRM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CHRM1 were set to 34212451; 31981491; 12483218 Phenotypes for gene: CHRM1 were set to Neurodevelopmental delay; intellectual disability; autism Review for gene: CHRM1 was set to AMBER Added comment: PMID: 34212451 - 2 unrelated cases with de novo missense variants (p.Pro380Leu and p.Phe425Ser), one case with early-onset refractory epilepsy, severe disability, and progressive cerebral and cerebellar atrophy, and the second case with mild dysmorphism, global developmental delay, and moderate intellectual disability. In vitro biochemical analyses of p.Pro380Leu demonstrated a reduction in protein levels, impaired cellular trafficking, and defective activation of intracellular signaling pathways. PMID: 31981491 - an autism spectrum disorder (no other information on phenotype, except ascertained to have severe neurodevelopmental delay) case with a de novo missense variant p.(Arg210Leu) PMID: 12483218 - null mouse model assessing memory demonstrated selective cognitive dysfunction. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1233 | KDM5C |
Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be updated from 'X-linked.. biallelic in females' to 'X-linked.. monoallelic in females may cause disease' at the next GMS panel update. A subset of female carriers have been shown to have impaired intellectual development and/or developmental delay (PMIDs: 10982473; 16538222; 18697827; 19826449; 21575681; 32279304) This also reflects the current MOI on all other relevant panels. |
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| Intellectual disability - microarray and sequencing v3.1220 | ARF3 |
Konstantinos Varvagiannis gene: ARF3 was added gene: ARF3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ARF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ARF3 were set to 34346499 Phenotypes for gene: ARF3 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system Penetrance for gene: ARF3 were set to unknown Review for gene: ARF3 was set to AMBER Added comment: Sakamoto et al (2021 - PMID: 34346499) provide some evidence that monoallelic ARF3 pathogenic variants may be associated with a NDD with brain abnormality. Using trio exome sequencing, the authors identified 2 individuals with NDD harboring de novo ARF3 variants, namely: NM_001659.2:c.200A>T / p.Asp67Val and c.296G>T / p.Arg99Leu. Individual 1 (with Asp67Val / age : 4y10m), appeared to be more severelely affected with prenatal onset progressive microcephaly, severe global DD, epilepsy. Upon MRI there was cerebellar and brainstem atrophy. Individual 2 (Arg99Leu / 14y) had severe DD and ID (IQ of 23), epilepsy and upon MRI cerebellar hypoplasia. This subject did not exhibit microcephaly. Common facial features incl. broad nose, full cheeks, small philtrum, strabismus, thin upper lips and abnormal jaw. There was no evidence of systemic involvement in both. ARF3 encodes ADP-ribosylation factor 3. Adenosine diphosphate ribosylation factors (ARFs) are key proteins for regulation of cargo sorting at the Golgi network, with ARF3 mainly working at the trans-Golgi network. ARFs belong to the small GTP-binding protein (G protein) superfamily. ARF3 switches between an active GTP-bound form and an inactive GDP-bound form, regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) respectively. Members of the ARF superfamily regulate various aspects of membrane traffic, among others in neurons. There are 5 homologs of ARF families, divided in 3 classes. ARF3 and ARF1 belong to class I. Monoallelic ARF1 mutations are associated with Periventricular nodular heterotopia 8 (MIM 618185). In vivo, in vitro and in silico studies for the 2 variants suggest that both impair the Golgi transport system although each variant most likely exerts a different effect (gain-of-function for Arg99Leu vs loss-of-function/dominant-negative for Asp67Val). This was also reflected in somewhat different phenotype of the subjects with the respective variants. Common features included severe DD, epilepsy and brain abnormalities although Asp67Val was associated with diffuse brain atrophy as well as congenital microcephaly and Arg99Leu with cerebellar hypoplasia. Evidence to support the effect of each variant include: Arg99Leu: Had identical Golgi localization to that of wt Had increased binding activity with GGA1, a protein recruited by the GTP-bound active form of ARF3 to the TGN membrane (supporting GoF) In silico structural analysis suggested it may fail to stabilize the conformation of Asp26, resulting in impaired GTP hydrolysis (GoF). In transgenic fruit flies, evaluation of the ARF3 variant toxicity using the rough eye phenotype this variant was associated with increased severity of the r-e phenotype similar to a previously studied GoF variant (Gln71Leu) Asp67Val: Did not show a Golgi-like pattern of localization (similar to Thr31Asn a previously studied dominant-negative variant) Displayed decreased protein stability In silico structural analysis suggested that Asp67Val may lead to compromised binding of GTP or GDP (suggestive of LoF) In transgenic Drosophila eye-specific expression of Asp67Val (similar to Thr31Asn, a known dominant-negative variant) was lethal possibly due to high toxicity in very small amounts in tissues outside the eye. There is no associated phenotype in OMIM, G2P or SysID. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1069 | PTPN4 |
Zornitza Stark gene: PTPN4 was added gene: PTPN4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033 Phenotypes for gene: PTPN4 were set to Intellectual disability Review for gene: PTPN4 was set to GREEN gene: PTPN4 was marked as current diagnostic Added comment: >3 unrelated probands and supportive mouse model PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1069 | SIN3B |
Zornitza Stark gene: SIN3B was added gene: SIN3B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SIN3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SIN3B were set to 33811806 Phenotypes for gene: SIN3B were set to Syndromic intellectual disability Review for gene: SIN3B was set to GREEN gene: SIN3B was marked as current diagnostic Added comment: PMID: 33811806 - 9 affected individuals, variants all de novo (2 PTCs, 2 missense, multigenic CNVs) - syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant ASD, congenital malformations, corpus callosum defects, and impaired growth. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1069 | DPYSL5 |
Zornitza Stark gene: DPYSL5 was added gene: DPYSL5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DPYSL5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DPYSL5 were set to 33894126 Phenotypes for gene: DPYSL5 were set to Neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities Review for gene: DPYSL5 was set to GREEN gene: DPYSL5 was marked as current diagnostic Added comment: Nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. The recurrent de novo p.Glu41Lys was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Both impaired DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.1012 | DOCK3 | Sarah Leigh Phenotypes for gene: DOCK3 were changed from Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292 to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia OMIM:618292; neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia MONDO:0032661 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.773 | OTUD5 | Zornitza Stark changed review comment from: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; to: PMID 33523931: Another 10 individuals from 7 families reported. Key features include poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.773 | OTUD5 | Zornitza Stark edited their review of gene: OTUD5: Added comment: PMID 33523931: Another 10 individuals from 7 families reported, promote to Green. X-linked multiple congenital anomalies-neurodevelopmental syndrome (MCAND) is an X-linked recessive congenital multisystemic disorder characterized by poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.; Changed rating: GREEN; Changed publications: 33131077, 33523931 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.761 | PIGF |
Zornitza Stark gene: PIGF was added gene: PIGF was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PIGF was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGF were set to 33386993 Phenotypes for gene: PIGF were set to Glycosylphosphatidylinositol deficiency, onychodystrophy, osteodystrophy, intellectual disability, and seizures Review for gene: PIGF was set to RED Added comment: The same homozygous missense variant identified in 2 individuals from different families from the same region of India. Individuals had a phenotype similar to DOORS syndrome without deafness. Impaired glycosylphosphatidylinositol (GPI) biosynthesis was demonstrated. Rated Red as the two families are likely to be related (founder mutation?). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.712 | GLS | Arina Puzriakova Phenotypes for gene: GLS were changed from Global developmental delay, progressive ataxia, and elevated glutamine, MIM# 618412 to Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.712 | GLS | Arina Puzriakova Added comment: Comment on phenotypes: Global developmental delay, progressive ataxia, and elevated glutamine, OMIM:618412; Global developmental delay, progressive ataxia, and elevated glutamine, MONDO:0032733; ?Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, OMIM:618339; Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, MONDO:0032685 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.694 | FBRSL1 |
Zornitza Stark gene: FBRSL1 was added gene: FBRSL1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FBRSL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FBRSL1 were set to 32424618 Phenotypes for gene: FBRSL1 were set to Intellectual disability; congenital anomalies Review for gene: FBRSL1 was set to GREEN gene: FBRSL1 was marked as current diagnostic Added comment: Three children with de novo PTCs that escape NMD, and an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. 2/3 had heart defects, cleft palate and hearing impairement. Supported by Xenopus oocyte functional studies Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.665 | SHMT2 |
Arina Puzriakova Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Sufficient number of unrelated cases (>3) with ID of relevant severity to this panel. Some functional data indicating variants result in impaired SHMT2 enzymatic function. Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag) SHMT2 is listed in Gene2Phenotype with a 'probable' disease confidence rating for 'SHMT2-related neurodevelopmental syndrome', and is also associated with 'Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, MIM# 619121' in OMIM. |
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| Intellectual disability - microarray and sequencing v3.647 | NARS | Arina Puzriakova reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.646 | NARS | Arina Puzriakova Phenotypes for gene: NARS were changed from Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.491 | ZIC1 | Arina Puzriakova Phenotypes for gene: ZIC1 were changed from CRANIOSYNOSTOSIS 6 to Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736; ?Craniosynostosis 6, 616602 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.489 | ZIC1 | Arina Puzriakova reviewed gene: ZIC1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 26340333, 30391508; Phenotypes: ?Craniosynostosis 6, 616602, Structural brain anomalies with impaired intellectual development and craniosynostosis, 618736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.432 | C2CD3 |
Arina Puzriakova changed review comment from: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function. - PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B. - PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases. - PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly. - PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease: Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs. Family 2: fetus with occipital encephalocele and a ventricular septal defect. Similar abnormalities were identified in another sib (also a terminated fetus), but DNA analysis was not performed on the latter. Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas.; to: - PMID: 24997988 (2014) - Two unrelated cases with OFD syndrome and biallelic variants (p.Arg62* and p.Cys1029Gly; p.Ala1304Valfs*3, respectively) in C2CD3. In a 4-year-old male, additional manifestations included severe microcephaly (-5 SD), severe ID, micropenis, and brain malformations including Molar Tooth Sign. In the second patient, a terminated foetus, severe microcephaly (-4 SD) was combined with canonical OFD symptoms, but assessment of ID was not possible. No functional studies of the variants; however, some data supporting a role of C2CD3 in cilium assembly and function. - PMID: 26092869 (2015) - Two unrelated individuals with biallelic variants in C2CD3. Clinical details are limited but both had features of Joubert syndrome (as JBTS screening study), as well as oral features including oral frenulae and/or cleft palate. No report on ID status, but could possibly be present in view of the JBTS diagnosis. One patient also harboured biallelic variants in TTC21B. - PMID: 26477546 (2015) - Compound het variants identified in two affected sibs with a classic form of JBTS and severe GDD but without any extraneural manifestations, as described in previous cases. - PMID: 27094867 (2016) - Two sibling fetuses with skeletal dysplasia, brain malformations but no microcephaly, in association with compound het variants in C2CD3. Due to termination of pregnancies, ID status could not be established. Analysis of patient-derived fibroblasts showed impaired cilium assembly. - PMID: 30097616 (2018) - Four individuals from three unrelated families with different biallelic variants in C2CD3. Each family exhibited distinct clinical phenotypes and severity of disease: Family 1: two sibs with a diagnosis of OFD including polydactyly, cleft palate and/or incomplete cleft lip, microcephaly, brain malformations and bilateral colobomas. GDD was noted in both sibs. Family 2: fetus with encephalocele and a ventricular septal defect. Similar abnormalities were identified in a sib (also a terminated fetus), but DNA analysis was not performed on the latter. Family 3: one male with various fetal anomalies, and subsequent diagnosis of JBTS following identification of consistent findings on brain MRI. Other features included DD and bilateral retina colobomas. |
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| Intellectual disability - microarray and sequencing v3.420 | SHMT2 |
Konstantinos Varvagiannis gene: SHMT2 was added gene: SHMT2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHMT2 were set to 33015733 Phenotypes for gene: SHMT2 were set to Congenital microcephaly; Infantile axial hypotonia; Spastic paraparesis; Global developmental delay; Intellectual disability; Abnormality of the corpus callosum; Abnormal cortical gyration; Hypertrophic cardiomyopathy; Abnormality of the face; Proximal placement of thumb; 2-3 toe syndactyly Penetrance for gene: SHMT2 were set to Complete Review for gene: SHMT2 was set to GREEN Added comment: García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants. All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs. Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones. SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF. Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes. While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction. Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect. The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity). Overall this gene can be considered for inclusion with (probably) green rating in gene panels for ID, metabolic / mitochondrial disorders, cardiomyopathy, congenital microcephaly, corpus callosum anomalies, etc. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.391 | MADD | Ivone Leong Phenotypes for gene: MADD were changed from to Neurodevelopmental disorder with dysmorphic facies, impaired speech and hypotonia, 619005; DEEAH syndrome, 619004 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.314 | LMNB1 |
Konstantinos Varvagiannis gene: LMNB1 was added gene: LMNB1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LMNB1 were set to 32910914 Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis Penetrance for gene: LMNB1 were set to unknown Mode of pathogenicity for gene: LMNB1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: LMNB1 was set to GREEN Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants. The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some. Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies). LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development. Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development. Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants. Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells). LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu). Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency). Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.280 | TRAPPC2L |
Arina Puzriakova gene: TRAPPC2L was added gene: TRAPPC2L was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TRAPPC2L was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAPPC2L were set to 30120216; 32843486 Phenotypes for gene: TRAPPC2L were set to Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331 Review for gene: TRAPPC2L was set to AMBER Added comment: Gene is associated with Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis in OMIM, but not in G2P. PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect. The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11. PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family. Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.196 | LYRM7 |
Arina Puzriakova changed review comment from: PMID: 24014394 (2013) - Homozygous variant (c.73G>A) in LYRM7 identified in a patient with normal initial development until the first 20 months of life, when she presented rapid deterioration which included severe psychomotor regression. Functional studies performed in yeast indicate functional impairment. PMID: 26912632 (2016) - Six distinct homozygous variants in the LYRM7 gene were identified in seven affected individuals (including 2 sibs). Initial cognitive development was delayed in three patients and borderline in one.; to: PMID: 24014394 (2013) - Homozygous variant (c.73G>A) in LYRM7 identified in a patient with normal initial development until the first 20 months of life, when she presented rapid deterioration which included severe psychomotor regression. Functional studies performed in yeast indicate functional impairment. PMID: 26912632 (2016) - Six distinct homozygous variants in the LYRM7 gene were identified in seven affected individuals (including 2 sibs). Initial cognitive development was delayed in three patients and borderline in one. Continued development was delayed to variable degrees in five individuals, and all were said to have impaired intelligence at the time of the most recent assessment (aged 2.5-16 yrs). PMID: 28694194 (2017) - Three affected family members with homozygosity for a splice site deletion (c.243_244+2delGAGT) in LYRM7. Development was normal for the first few months of life, however all experienced a rapidly progressive clinical course which included profound impairment of psychomotor and mental functions. |
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| Intellectual disability - microarray and sequencing v3.183 | ADD3 |
Arina Puzriakova changed review comment from: Biallelic missense variants identified in four families (ten affected patients). Not associated with any phenotype in G2P. OMIM entry currently based on PMID:23836506. PMID: 23836506 (2013) - Homozygous missense variant c.1100G>A (p.G367D). ADD3 first identified in a consanguineous Jordanian family affecting four members. ID severe in two individuals and moderate/borderline in the others, some functional work from fibroblasts. The paper focused on the main phenotype of inheritable cerebral palsy. ; to: Biallelic missense variants identified in four families (ten affected patients). Not associated with any phenotype in G2P. OMIM entry currently based on PMID: 23836506. PMID: 23836506 (2013) - Homozygous missense variant c.1100G>A (p.G367D). ADD3 first identified in a consanguineous Jordanian family affecting four members. ID severe in two individuals and moderate/borderline in the others, some functional work from fibroblasts. The paper focused on the main phenotype of inheritable cerebral palsy. PMID: 29768408 (2018) - Two families with ADD3 biallelic variants and one family with ADD3 and KAT2B missense variants. Individuals with ADD3 variants have similar phenotypes and individuals with KAT2B variants have an extension to phenotype with impaired kidney and heart function, also demonstrated with functional evidence in flies. ID was reported in 5/6 participants. |
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| Intellectual disability - microarray and sequencing v3.170 | KIF21B |
Konstantinos Varvagiannis gene: KIF21B was added gene: KIF21B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KIF21B were set to 32415109 Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly Penetrance for gene: KIF21B were set to unknown Mode of pathogenicity for gene: KIF21B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: KIF21B was set to GREEN Added comment: Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.170 | TMEM106B |
Konstantinos Varvagiannis gene: TMEM106B was added gene: TMEM106B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TMEM106B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TMEM106B were set to 29186371; 29444210; 32595021 Phenotypes for gene: TMEM106B were set to Leukodystrophy, hypomyelinating, 16 (MIM #617964) Penetrance for gene: TMEM106B were set to Complete Mode of pathogenicity for gene: TMEM106B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: TMEM106B was set to GREEN Added comment: 6 unrelated individuals with Leukodystrophy, hypomyelinating, 16 (MIM #617964) due to a recurrent TMEM106B variant have been reported to date in the literature (Simons et al 2017 - PMID: 29186371, Yan et al 2018 - PMID: 29444210, Ikemoto et al 2020 - PMID: 32595021). While a 3 y.o. female described by Yan et al had DD (eg sitting at 9m, walking at 25m) with normal cognitive functioning, and a 38 y.o. female had borderline intellectual functioning (IQ 76), 4 affected individuals had ID. Among them, a 19 y.o. male with severe ID was also found to harbor a second de novo possibly damaging USP7 variant. Seizures have been reported in 2 unrelated subjects. [Clinical features are also summarized in table 1 - Ikemoto et al]. All harbored NM_001134232.2(TMEM106B):c.754G>A (p.Asp252Asn) which in almost all cases occurred as a de novo event. In a single case this variant was inherited from a mosaic parent with mild DD in infancy but normal cognition (reported by Simons et al). As discussed by Ito et al (2018 - PMID: 30643851) the encoded protein is a structural component of the lysosomal membrane, playing a role on lysosome acidification. Acidity of the lysosome mediates multiple aspects of lysosomal function. Ito et al, using patient-derived fibroblasts assessed mRNA and protein levels. These were unaltered compared with controls. While TMEM106B had been previously shown to affect lysosome number, morphology and acidification, Ito et al demonstrated increased number of lysosomes in patient cells as well as impaired acidification compared to controls. As commented lysosomes are required for generation of myelin. Recurrence of this missense variant, the presence of pLoF TMEM106B variants in gnomAD as well as the phenotypically normal Tmem106b null mice suggest that this variant may have a gain-of-function or dominant negative effect. Genes for other forms of hypomyelinating lipodystrophy (incl. PLP1) have green rating in the ID panel. Overall TMEM106B can be considered for the ID panel with green rating and the epilepsy panel with amber rating. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.170 | EXOC2 |
Konstantinos Varvagiannis gene: EXOC2 was added gene: EXOC2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: EXOC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOC2 were set to 32639540 Phenotypes for gene: EXOC2 were set to Global developmental delay; Intellectual disability; Abnormality of the face; Abnormality of brain morphology Penetrance for gene: EXOC2 were set to Complete Review for gene: EXOC2 was set to AMBER Added comment: Van Bergen et al (2020 - PMID: 32639540) report on 3 individuals from 2 families, harboring biallelic EXOC2 mutations. Clinical presentation included DD, ID (severe in 2 subjects from fam1, borderline intellectual functioning in fam2), dysmorphic features and brain abnormalities. Cerebellar anomalies were common to all with a molar tooth sign observed in one (1/3). Other findings limited to subjects from one family included acquired microcephaly, congenital contractures, spastic quadriplegia (each observed 2/3). Previous investigations were in all cases non-diagnostic. WES identified biallelic EXOC2 mutations in all affected individuals. EXOC2 encodes an exocyst subunit. The latter is an octameric complex, component of the membrane transport machinery, required for tethering and fusion of vesicles at the plasma membrane. As discussed ,vesicle transport is important for the development of brain and the function of neurons and glia. Exocyst function is also important for delivery of Arl13b to the primary cilium (biallelic ARL13B mutations cause Joubert syndrome 8) and ciliogenesis. Affected subjects from a broader consanguineous family (fam1) were homozygous for a truncating variant. Fibroblast studies revealed mRNA levels compatible with NMD (further restored in presence of CHX) as well as reduced protein levels. The female belonging to the second non-consanguineous family was found to harbor 2 missense variants in trans configuration. An exocytosis defect was demonstrated in fibroblasts from individuals belonging to both families. Ciliogenesis appeared to be normal, however Arl13b localization/recruitment to the cilia was reduced compared with control cells with the defect rescued upon exogenous expression of wt EXOC2. Mutations in other genes encoding components of the exocyst complex have been previously reported in individuals with relevant phenotypes (e.g. EXOC8 in a boy with features of Joubert s. or EXOC4 in nephrotic syndrome). The authors discuss on the essential role of EXOC2 based on model organism studies (e.g. impaired neuronal membrane traffic, failure of neuronal polarization and neuromuscular junction expansion seen in Drosophila Sec5 (EXOC2) null mutants). Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.33 | VPS51 |
Zornitza Stark gene: VPS51 was added gene: VPS51 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS51 were set to 30624672; 31207318 Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606 Review for gene: VPS51 was set to AMBER Added comment: Two families reported with bi-allelic variants in this gene and global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.31 | WIPI2 |
Zornitza Stark gene: WIPI2 was added gene: WIPI2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: WIPI2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WIPI2 were set to 30968111 Phenotypes for gene: WIPI2 were set to Intellectual developmental disorder with short stature and variable skeletal anomalies 618453 Review for gene: WIPI2 was set to RED Added comment: Four homozygous individuals from one consanguineous family with intellectual disability, short stature and variable skeletal anomalies. Functional studies in patient cells showed impaired protein function. One to watch. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.3 | ZIC1 | Zornitza Stark reviewed gene: ZIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26340333, 30391508; Phenotypes: Structural brain anomalies with impaired intellectual development and craniosynostosis, OMIM #618736; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | SLC9A7 |
Zornitza Stark gene: SLC9A7 was added gene: SLC9A7 was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: SLC9A7 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SLC9A7 were set to 30335141 Phenotypes for gene: SLC9A7 were set to Intellectual developmental disorder, X-linked 108; OMIM #301024 Review for gene: SLC9A7 was set to AMBER Added comment: 6 males from 2 unrelated families with hemizygous missense mutation in the SLC9A7 gene. The mutation segregated with the disorder in the family. In vitro functional expression studies in CHO cells (AP-1 cells) showed that the mutation caused decreased levels of protein expression and reduced oligosaccharide maturation/glycosylation compared to wildtype, indicating impaired posttranslational processing. Subcellular localization studies indicated that protein trafficking was unaffected by the mutation. However, examination of the trans-Golgi compartment suggested a gain-of-function effect and a perturbation of glycosylation of secretory cargo. Serum transferrin studies in 1 patient suggested a glycosylation defect. One to watch. Sources: Expert list |
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| Intellectual disability - microarray and sequencing v3.0 | TET3 |
Konstantinos Varvagiannis gene: TET3 was added gene: TET3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TET3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TET3 were set to https://doi.org/10.1016/j.ajhg.2019.12.007 Phenotypes for gene: TET3 were set to Global developmental delay; Intellectual disability; Macrocephaly; Growth abnormality; Seizures; Autistic behavior; Abnormality of movement; Abnormality of the face Penetrance for gene: TET3 were set to Complete Review for gene: TET3 was set to GREEN Added comment: Beck et al (2020 - DOI: https://doi.org/10.1016/j.ajhg.2019.12.007) report on individuals with monoallelic de novo or biallelic pathogenic TET3 variants. For both inheritance modes (AR/AD) DD/ID were among the observed features (mild-severe - individuals from families 2, 4 and 6 for whom presence of ID was not commented, relevance to the current panel is suggested from the developmental milestones in the supplement. One individual presented DD without ID). Other features included hypotonia (in 8), ASD/autistic features (in 5), seizures (2 unrelated subjects for each inheritance mode). Postnatal growth abnormalities were observed in many, in most cases involving head size (with/without abnormal stature) and few presented abnormal prenatal growth. Variable movement disorders were observed in some. Some facial features appeared to be more common (eg. long face, tall forehead, etc). Most were referred for their DD. Extensive prior genetic investigations had (mostly) come out normal (with possible contribution of a 16p11.2 dup in an individual with monoallelic variant or a 16q22 dup in another with biallelic TET3 variants). Monoallelic / biallelic variants in all subjects were identified following exome sequencing. TET3 encodes a methylcytosine dioxygenase (the TET family consisting of 3 enzymes, TET1, TET2, TET3). These enzymes are involved in DNA demethylation through a series of reactions beginning with the conversion of 5-methyl cytosine [5mc] to 5-hydromethylcytosine [5hmC]. 5 individuals from 3 families (1/3 consanguineous) harbored biallelic missense variants. 5 different missense variants were observed. Heterozygous parents appeared to be mildly affected (eg. having learning difficulties, etc). 6 individuals from 5 families harbored monoallelic variants [3 truncating (of which 2 localizing in the last exon), 2 missense SNVs]. In one family the variant was inherited from a similarly affected parent. In all other cases the variant had occured de novo. No additional TET3 variants were identified, with the limitations of WES. All missense mutations, whether observed in individuals with biallelic or monoallelic variants, were located within the catalytic domain or - for a single variant (NM_001287491.1:c.2254C>T / p.Arg752Cys) - adjacent to it. Functional studies were carried out only for (all) missense variants observed in individuals with biallelic variants. Conversion of 5mC to 5hmC is the first step in DNA demethylation. In HEK293 cells overexpressing either wt or variants, production of 5hmc was measured. 4/5 missense variants evaluated demonstrated a defect in converting 5mC to 5hmC, Arg752Cys being an exception (as also predicted by its localization). DD/ID and abnormal growth are also features of disorders of the epigenetic machinery (DNA methylation machinery, histone machinery, chromatin remodelers, other chromatin-associated proteins). Similarly to TET3, both monoallelic and biallelic variants in KDM5B, encoding for another component of the epigenetic machinery, have been identified in individuals with ID. Mouse models discussed by the authors [several Refs provided though not here reviewed] : The gene has been shown to be highly expressed in oocytes, zygotes and neurons and to play a role in demethylation of the paternal genome after fertilization. (From the MGI: 'mice inheriting a null allele from a germ cell conditional null mother display impaired reprogramming of the paternal genome resulting in reduced embryo viability'). Beck et al also note that Tet3 inhibition or depletion in differentiated neurons can impact synaptic function [PMIDs cited: 25915473, 24757058, 26711116]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.0 | DLL1 |
Konstantinos Varvagiannis gene: DLL1 was added gene: DLL1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DLL1 were set to 31353024 Phenotypes for gene: DLL1 were set to Global developmental delay; Intellectual disability; Morphological abnormality of the central nervous system; Seizures; Behavioral abnormality; Autism; Scoliosis Penetrance for gene: DLL1 were set to unknown Review for gene: DLL1 was set to GREEN Added comment: Heterozygous DLL1 pathogenic variants cause Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (# 618709). Fischer-Zirnsak et al (2019 - PMID: 31353024) reported on 15 affected individuals from 12 unrelated families. Most common features included DD/ID (12/14), ASD (6/14 - belonging to 6 families) or other behavioral abnormalities, seizures (6/14 - from 6 unrelated families) and various brain MRI abnromalities. As commented by OMIM (based on the same ref) "Cognitive function ranges from severely impaired to the ability to attend schools with special assistance". Among other features, scoliosis was observed in 4. The authors could not identify a distinctive facial gestalt. Variable initial investigations (where discussed/performed - also suggesting relevance to the current panel) included CMA, FMR1, FLNA, mitochondrial DNA analysis and metabolic work-up but had not revealed an alternative cause. The DLL1 variants were identified by WES (with the exception of a 122-kb microdeletion spanning DLL1 and FAM120B detected by CMA). Nonsense, frame-shift, splice-site variants in positions predicted to result to NMD were identified in most. One individual was found to harbor a missense variant (NM_005618.3:c.536G>T / p.Cys179Phe) and another the aforementioned microdeletion. The variant in several individuals had occurred as a de novo event. In 2 families, it was inherited from an also affected parent (an unaffected sib was non-carrier) while in 3 families parental studies were not possible/complete. In frame insertion of 4 residues was demonstrated for a splice site variant, from LCLs of the corresponding individual. For another individual, material was unavailable for mRNA studies. The missense variant affected a cysteine (of the DSL domain) conserved in all Notch ligands while AA changes affecting the same position of JAG1 (another Notch ligand) have been described in patients with Alagille s. Based on the variants identified and reports of deletions spanning DLL1 in the literature, haploinsufficiency is the proposed underlying mechanism. The gene has also a pLI of 1 and %HI of 4.65. DLL1 encodes the Delta-like canonical Notch ligand 1. Notch signaling is an established pathway for brain morphogenesis. Previous in vivo and in vitro studies have demonstrated the role of DLL1 in CNS. The gene is highly expressed in neuronal precursor cells during embryogenesis. Expression of Dll1 (and other molecules of the Notch signalling pathway) in an oscillatory/sustained pattern and cell-cell interactions important for this pathway have been demonstrated to play a role in neuronal differentiation. [Most discussed by Fischer-Zirnsak et al with several refs provided / also Gray et al., 1999 - PMID: 10079256 & OMIM]. Animal models as summarized by the authors: [Mouse] Loss of Dll1 in mice has been shown to increase neuronal differentiation, cause CNS hyperplasia and increased number of neurons (PMIDs cited: 9109488, 12397111, 20081190). Reduced Dll1 expression was associated with scoliosis and mild vertebral defects (cited PMIDs: 19562077, 14960495, 22484060 / among others Dll1 haploinsufficiency and dominant negative models studied). Scoliosis and vertebral segmentation defects were features in 4 and 1 individual, respectively in the cohort of 15. [Zebrafish] Homozygous mutations in dlA, the zebrafish ortholog, disrupted the Delta-Notch signaling and led to patterning defects in the hindbrain and overproduction of neurons (cited: 15366005). Please consider inclusion in other possibly relevant panels e.g. for ASD. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.0 | MN1 |
Konstantinos Varvagiannis gene: MN1 was added gene: MN1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MN1 were set to 31834374; 31839203; 15870292 Phenotypes for gene: MN1 were set to Central hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Hearing impairment; Abnormality of facial skeleton; Craniosynostosis; Abnormality of the face; Abnormality of the cerebellum; Abnormality of the corpus callosum; Polymicrogyria Penetrance for gene: MN1 were set to Complete Review for gene: MN1 was set to GREEN Added comment: Two studies by Mak et al (2019 - PMID: 31834374 / Ref1) and Miyake et al (2019 - PMID: 31839203 / Ref2) provide sufficient evidence for heterozygous MN1 C-terminal truncating variants (predicted to escape NMD - localizing within the last nucleotides of exon 1 or in exon 2) being associated with a distinctive phenotype and DD and ID among the features. Mak et al also discuss on the phenotype of individuals with variants causing N-terminal truncation or with MN1 deletions (discussed at the end of this review). Overlapping features for C-terminal truncating variants included hypotonia, feeding difficulties, global DD and ID, hearing loss, cranial shape defects (/craniosynostosis in few), highly suggestive/distinctive facial features (eg. frontal bossing, hypertelorism, downslanting palpebral-fissures, shallow orbits, short upturned nose, low-set/posteriorly rotated/dysplastic ears, etc) and brain MRI abnormalities (eg. rhomboencephalosynapsis or cerebellar dysplasia, polymicrogyria, dysplastic CC). The majority of the affected individuals were investigated by WES/WGS with a single one tested by targeted MN1 Sanger sequencing due to highly suggestive features. Variable previous investigations incl. CMA in several, gene panel testing (Rasopathies, hearing loss, craniofacial panels, FMR1, etc) and metabolic work were normal in most. In a single case a likely pathogenic ACSL4 also explained part of the phenotype (Ref2). In the majority of these individuals, the variant had occured as a de novo event. Two sibs had inherited the truncating variant from a milder affected mosaic parent. A parental sample was not available for an additional individual. p.(Arg1295*) or NM_002430.2:c.3883C>T was a recurrent variant, seen in several individuals and in both studies. Several lines of evidence are provided for the MN1 variants and the role of the gene including: - For few individuals for whom cell lines were available, variants were shown to escape NMD by cDNA/RT-PCR/RNA-seq [Ref1 & 2]. - The gene has a high expression in fetal brain [Ref2 / fig S2] - MN1 (* 156100 - MN1 protooncogene, transcriptional regulator) has been proposed to play a role in cell proliferation and shown to act as transcription cofactor (increasing its transactivation capacity in synergy with coactivators EP300 and RAC3) [Discussion and Refs provided in Ref2]. - In vitro studies suggested increased protein stability (upon transfection of wt/mut constructs in HEK293T cells), enhanced MN1 aggregation in nuclei (when wt/mut GFP-tagged MN1 was expressed in HeLa cells), increased inhibitory effect on cell growth (MG63 cells - role of MN1 in cell proliferation discussed above) and retained transactivation activity (upon transient MN1 overexpression of wt/mt MN1 in HEK293T cells) for the variants. These seem to support a gain-of-function effect for the C-terminal truncating variants [Ref2]. - The truncating variants are proposed to raise the fraction of Intrinsically disordered regions (IDRs = regions without fixed tertiary structure) probably contributing to the above effects [Ref2]. - Expression of FLAG-tagged MN1 wt/mut MN1 followed by immunoprecipitation and mass spectrometry analysis (mCAT-Hela cells), provided evidence that MN1 is involved in transcriptional regulation: a. through binding ZBTB24 and RING1 E3 ubiquitin ligase (with mutant MN1 displaying impaired interaction with ZBTB24 and no binding to RING1) and/or b. through interaction with DNA-binding transcription factors PBX1 and PKNOX1. Proper MN1 degradation is proposed to mediate precise transcriptional regulation. [Ref2] - Transcriptome analysis in LCLs from an affected individual suggested dysregulation of genes relevant to neuronal development (eg. LAMP, ITGA, etc) and GO analysis suggested enrichment for pathways possibly linked to the observed phenotypes [Ref2]. - Discussed in both Refs1/2, homozygous Mn1-ko mice display abnormal skull bone development and die at/shortly after birth as a result of cleft palate. Heterozygous Mn1-ko mice display hypoplastic membranous bones of the cranial skeleton and cleft palate (CP), the latter with incomplete penetrance [Meester-Smoor et al 2005 - PMID: 15870292]. This is thus compatible with the cranial shape defects observed in C-terminal truncations (while CP has been reported in gene deletions, bifid uvula was reported once in C-terminal and N-terminal truncating variants, in the latter case with submucous CP). ----- The phenotype of other MN1 variants is discussed by Mak et al (Ref1) : - 3 individuals with MN1 N-terminal truncating variants (eg. Ser179*, Pro365Thrfs*120, Ser472*) presented speech delay, mild conductive hearing loss and facial features different from C-terminal truncations. None of these individuals had significant ID. - Microdeletions: One individual (#27) with 130 kb deletion harboring only MN1, presented microcephaly, DD and ID and mildly dysmorphic facial features. Deletions spanning MN1 and other genes (eg a 1.17 Mb deletion in ind. #28) and relevant cases from the literature reviewed, with mild DD/ID, variable palatal defects and/or facial dysmorphisms (distinct from the C-terminal truncating variants) among the frequent findings. [Please consider inclusion in other possibly relevant gene panels eg. for hearing loss (conductive/sensorineural in 16/20 reported by Mak et al) or craniosynostosis, etc]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.0 | KAT8 |
Konstantinos Varvagiannis gene: KAT8 was added gene: KAT8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: KAT8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: KAT8 were set to 31794431 Phenotypes for gene: KAT8 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of vision; Feeding difficulties; Abnormality of the cardiovascular system; Autism Penetrance for gene: KAT8 were set to unknown Review for gene: KAT8 was set to GREEN Added comment: Heterozygous pathogenic missense KAT8 variants have been reported in individuals with DD, ID and epilepsy. Variants occurred as de novo events within the chromobarrel or the acetyltransferase domain and were all shown to affect H4K16 acetylation, as would be predicted by the gene's function (lysine acetyltransferase). Evidence from brain specific Kat8 knockout in mouse, supports the role of the gene in brain development. One similarly affected individual compound heterozygous for a nonsense and a missense variant (the former affecting subnuclear localization and the latter H4K16ac) was also reported, with carrier relatives being unaffected. Mutations in genes of the MSL/NSL complexes (with which KAT8 forms multisubunit complexes) or genes in other acetyltransferases of the same subfamily (MYST) as KAT8 cause neurodevelopmental disorders [Details provided below]. ----- Li et al. (2019 - PMID: 31794431) report on 8 unrelated individuals with heterozygous de novo pathogenic KAT8 variants, as well as an additional one compound heterozygous for a nonsense and a missense one. Overlapping phenotype consisted of DD/ID (8/8), seizures/epilepsy (6/8), brain MRI anomalies as well as presence of variable facial dysmorphic features. Less frequent features included abnormal vision (5/8), feeding difficulties (3/8), cardiac anomalies (3/8), autism (in 1). The (9th) individual with biallelic variants had similar phenotype of DD/ID, epilepsy, autism and dysmorphic facial features. Heterozygous parents and sister, the latter carrier for the missense variant, were all unaffected. All individuals had undergone exome sequencing, while extensive other investigations for at least 7/9 had only revealed variants of uncertain significance/contribution to the phenotype or were normal. KAT8 encodes lysine acetyltransferase 8, which acetylates histone H4 at lysine 16 (H4K16). It belongs to the MYST subfamily of lysine acetyltransferases, the other members of which include KAT6A, KAT6B (both involved in neurodevelopmental disorders) and KAT5. KAT8 forms two stoichiometric multisubunitcomplexes, one with the MSL complex and the other with the NSL. Mutations in genes encoding for subunits of the NSL or MSL complex (eg. KANSL1 and MSL3) are associated with neurodevelopmental disorders. Overall 6 missense SNVs were reported among the heterozygous patients, p.Tyr90Cys (NM_032188.2:c.269A>G) being a recurrent one seen in 3. The compound heterozygous patient had a missense (c.973C>T / p.Arg325Cys) and a nonsense variant (c.523A>T / p.Lys175*). All missense variants lied either in the chromobarrel domain or the acetyltransferase domain. Variants in the latter domain localized within the KAT8/Mof-specific region or - in the case of the compound heterozygous individual - within the acetyl-CoA binding motif. FLAG-tagged KAT8 (either wt or for all missense SNVs) was transfected in HEK293 cells with vectors for HA-tagged MSL proteins. While the nonsense variant was difficult to express, missense SNVs were expressed to similar levels to wt, promoted expression of MSL proteins but resulted in defective H4K16 acetylation and to a lesser extent H4K5 acetylation. As a result all missense variants impaired acetylation. This was also the case for chromobarrel domain variants, while expression of a KAT8 lacking the chromobarrel domain confirmed its ability to form complex with the MSL proteins and the impairment of H4K16 acetylation. The nonsense variant demonstrated abnormal subnuclear localization. The mouse model provides extensive evidence for the involvement of KAT8 in cerebral development. Cerebrum-specific Kat8 knockout mice presented postnatal growth retardation, hyperactivity/irritability, pre-weaning lethality, and cerebral hypoplasia upon autopsy. Loss of Kat8 reduced the number of neural stem and progenitor cells available for embryonic cerebrocortical development, impaired cell proliferation and stimulated apoptosis. The article also provides additional evidence from mouse model. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.0 | RARS |
Konstantinos Varvagiannis gene: RARS was added gene: RARS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RARS were set to 31814314; 28905880; 24777941 Phenotypes for gene: RARS were set to Cerebral hypomyelination; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Nystagmus; Ataxia; Feeding difficulties Penetrance for gene: RARS were set to Complete Review for gene: RARS was set to GREEN Added comment: Biallelic pathogenic RARS1 variants cause Leukodystrophy, hypomyelinating, 9 (# 616140). The current review was based primarily on PMID: 31814314 (Mendes et al, 2019) providing details on 20 affected individuals from 15 families. 5 of these patients were included in a previous publication (Wolf et al, 2014 - PMID: 24777941) sharing authors with this study. Clinical presentation and severity can be highly variable. However, among the 15 patients of relevant age (5/20 deceased at an early age), ID was observed in 13 (in 6/13 mild-moderate, in 7/13 severe/profound). Epilepsy was reported in half (10/20) with seizures being refractory to treatment in most and the phenotype corresponding to an infantile epileptic encephalopathy. DD and seizures were the presenting feature in 7 and 5 patients respectively, while in other cases presenting features were less specific (eg. failure to thrive in 1/20, irritabilty in 2/20). As a result the gene appears to be relevant to both DD/ID and epilepsy panels. RARS1 encodes the cytoplasmic arginyl-tRNA synthetase 1, which is a component of the aminoacyl-tRNA synthetase complex (OMIM and Wolf et al, 2014 - PMID: 24777941). Aminoacyl-tRNA synthetases catalyze the aminoacylation ('charging') of tRNA by (with) their cognate amino acid. Utilisation of alternative initiation codons, from a single mRNA transcript, results in translation of a long and a short protein isoform (Zheng et al 2006 - PMID: 16430231). The long isoform is needed for the formation of the multi-synthetase complex (MSC), while the short is free in the cytoplasm and does not have any interaction with the MSC. The long isoform appears to be essential for protein synthesis (discussed with several refs provided in PMID: 28905880 - Nafisinia et al, 2017). The role of variants has been supported in several patients by additional studies - among others : [PMID 31814314] Impaired Arginyl-tRNA synthetase activity was demonstrated in fibroblasts from 3 patients. Activity was normal in one additional individual compound heterozygous for a variant affecting initiation codon and a missense one. Western blot however demonstrated presence mainly of the short protein isoform. The authors suggest that this isoform possibly contributed to enzymatic activity. The long isoform which is needed for the MSC complex was only represented by a faint band in the Western Blot of the same individual. [PMID: 28905880] Using fibroblasts from an affected subject homozygous for a missense variant (NM_002887.3:c.5A>G / p.Asp2Gly) and controls, a 75% reduction of the long isoform was shown upon WB. The short isoform was present at similar levels. As the N-terminus (of the long isoform) mediates interaction with the MSC (and AIMP1), assembly of the latter was 99% reduced in patient fibroblasts. Proliferation of patient fibroblasts was significantly reduced when cultured in a medium with limited arginine, a finding which was thought to reflect inefficient protein synthesis. Mutations in other genes encoding for aminoacyl-tRNA synthetases (eg. AARS1, VARS1) or scaffolding proteins of the multisynthetase complex (eg. AIMP1 and AIMP2) lead to neurodevelopmental disorders with overlapping phenotype [most genes rated green in both the ID and epilepsy panel]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1143 | AFF3 |
Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence. The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy]. 9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13. AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development. Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot. Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study]. Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects. Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant. Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3. ---- Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)]. ---- In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM. Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel). ---- As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article). [Review modified to add additional reference/case report]; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb deletion affecting only AFF3 (LAF4) and removing also this sequence. The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy]. 9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13. AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development. Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot. Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study]. Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects. Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant. Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3. ---- Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)]. ---- In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM. Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel). ---- As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article). [Review modified to add additional reference/case report] |
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| Intellectual disability - microarray and sequencing v2.1135 | TRAPPC4 |
Konstantinos Varvagiannis gene: TRAPPC4 was added gene: TRAPPC4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TRAPPC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAPPC4 were set to 31794024 Phenotypes for gene: TRAPPC4 were set to Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment Penetrance for gene: TRAPPC4 were set to Complete Review for gene: TRAPPC4 was set to GREEN Added comment: Van Bergen et al. (2019 - PMID: 31794024) report on 7 affected individuals from 3 famillies (only 1 of which consanguineous), all homozygous for a TRAPPC4 splicing variant. Overlapping features included feeding difficulties, progressive microcephaly, severe to profound developmental disability (7/7 - DD also prior to the onset of seizures / regression also reported in 3), epilepsy (7/7 - onset in the first year), spastic quadriparesis. Other findings in some/few incl. scoliosis, cortical visual and hearing impairment. Some facial features were shared (eg. bitemporal narrowing, long philtrum, open mouth with thin tented upper lip, pointed chin, etc). Brain imaging demonstrated abnormalities in those performed (among others cerebral with/without cerebellar atrophy). Work-up prior to exome sequencing was normal (highly variable incl. metabolic testing, CMA, MECP2, CDKL5, mitochondrial depletion studies, etc). Exome of affected individuals (and parents +/- affected sibs in some families) revealed a homozygous TRAPPC4 splicing variant [NM_016146.5:c.454+3A>G / chr11:g.118890966A>G (hg19)]. Sanger sequencing confirmed variant in affecteds, heterozygosity in parents and compatible genotypes with disease status in sibs/other members. Families were of Caucasian/Turkish and French-Canadian ethnicities. SNP array to compare haplotypes between affecteds in 2 families did not reveal a shared haplotype (/founder effect) and the variant is present in gnomAD (68/281054 - no hmz) in many populations (European/Asian/African/Latino) [https://gnomad.broadinstitute.org/variant/11-118890966-A-G]. mRNA studies in fibroblasts from an affected individual confirmed the splicing defect (2 RT-PCR products corresponding to wt and a shorter due to skipping of exon 3, the latter further confirmed by Sanger sequencing. The shorter transcript is not present in controls). qPCR revealed that the normal transript in patient fibroblasts was present at 6% of the level observed in control fibroblasts (or 54% in the case of a heterozygote parent compared to controls). Western blot in patient fibroblasts, revealed presence of full-length protein in significantly reduced levels compared to fibroblasts from carrier parents or controls. There was no band using an antibody targeting the N-terminal region of the protein prior to exon 3, suggesting that NMD applies (skipping of ex3 is also predicted to lead to frameshift). TRAPPC4 encodes one of the core proteins of the TRAPP complex. Use of different accessory proteins leads to formation of 2 distinct complexes (TRAPPII / III). The complex has an important role in intracellular trafficking. Both TRAPPII & TRAPPIII have a function in the secretory pathway, while complex III has a role also in autophagy. Core proteins are important for the complex stability. The TRAPP complex serves as a GEF for Ypt/Rab GTPases [several refs in article]. Mutations in genes for other proteins of the complex lead to neurodevelopmental disorders with associated ID ('TRAPPopathies' used by the authors / TRAPPC12, C6B, C9 green in the current panel). Western blot suggested that levels of other TRAPP subunits (TRAPPC2 or C12) under denaturing conditions, although PAGE/size exclusion chromatography suggested that the levels of fully-assembled TRAPP complexes were lower in affected individuals. Studies in patient fibroblasts showed a secretory defect (between ER, Golgi and the plasma membrane) which was restored upon lentiviral transduction with wt TRAPPC4 construct. Basal and starvation-induced autophagy were also impaired in patient fibroblasts (increased LC3 marker and LC3-positive structures / impaired co-localization with lysosomes) partly due to defective autophagosome formation (/sealing). TRAPPC4 is the human orthologue of the yeast Trs23. In a yeast model of reduced Trs23 (due to temperature instability) the authors demonstrated impaired assembly of the TRAPP core. The yeast model recapitulated the autophagy as well as well as the secretory defect observed in patient fibroblasts. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1135 | SLC5A6 |
Konstantinos Varvagiannis changed review comment from: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature; to: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1135 | SLC5A6 |
Konstantinos Varvagiannis gene: SLC5A6 was added gene: SLC5A6 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC5A6 were set to 27904971; 31392107; 31754459; 23104561; 29669219 Phenotypes for gene: SLC5A6 were set to Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis Penetrance for gene: SLC5A6 were set to Complete Review for gene: SLC5A6 was set to GREEN Added comment: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1134 | OXR1 |
Konstantinos Varvagiannis gene: OXR1 was added gene: OXR1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: OXR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OXR1 were set to https://doi.org/10.1016/j.ajhg.2019.11.002 Phenotypes for gene: OXR1 were set to Central hypotonia; Global developmental delay; Delayed speech and language development; Intellectual disability; Seizures; Abnormality of the cerebellum Penetrance for gene: OXR1 were set to Complete Review for gene: OXR1 was set to GREEN Added comment: Wang et al (2019 - https://doi.org/10.1016/j.ajhg.2019.11.002 ) report on 5 individuals (from 3 families) with biallelic OXR1 LoF variants. Common features included hypotonia (4/5), severe global DD (5/5) and speech delay (5/5), ID (5/5), epilepsy (5/5) with cerebellar dysplasia/atrophy (5/5) and in some scoliosis. All were investigated by exome sequencing and were found to harbor biallelic loss-of-function variants (2 splice-site, a stopgain and a frameshift one) either in homozygosity (2 consanguineous families) or in compound heterozygosity. In all cases parental segregation studies were compatible and in one family, an unaffected sib shown to be carrier. Althouhgh OXR1 has been shown to affect several processes (among others DNA lesions induced by oxidative stress in E.coli, neuronal maintenance, mitochondrial morphology and DNA maintenance, etc), its mechanism of action is still not well defined. There are 6 RefSeq transcripts, the longest (NM_018002.3) encoding 3 protein domains (LysM, GRAM, TLDc). The TLDc domain is encoded by all transcripts. Identified variants affected (probably all - fig1D) transcripts expressed in the CNS, namely NM_018002.3, NM_001198532.1, NM_181354.4. The 3 transcripts not expressed in the CNS are NM_001198533.1, NM_001198534.1 and NM_001198535.1. Western blot with 2 different antibodies which would bind upstream of the truncation site failed to detect presence of truncated proteins in 2 affected individuals from 2 families. The Drosophila homolog of OXR is mustard (mtd). The authors provide evidence that loss of mtd is lethal. This was however rescued by expression of an 80kb fly BAC clone covering mtd, or the fly mtd-RH isoform cDNA, or a short human OXR1 cDNA containing only the TLDc domain or a human NCOA7 cDNA. The latter is another human mtd homolog which also contains the TLDc domain. As a result the TLDc domain compensated sufficiently for loss of mtd. Flies that survived displayed bang sensitivity and climbing defects the former assay being suggestive of susceptibility to seizures and the latter of impaired neurological/muscular function. The authors provided evidence that mtd is broadly expressed in the fly CNS. RNAi mediated mtd knockdown specific to neurons (elav/nSyb-GAL4 expression of mtd RNAi) led to lethal eclosion defects for RNAis targeting most (18)/all(23) mtd isoforms. Lifespan was increased upon expression of human OXR1 cDNA. Neuronal loss and vacuolization was demonstrated and additional experiments in R7 photoreceptors showed presence of aberrant lysosomal structures (autolysosomes, autophagosomes and/or endolysosomes). Aberrant lysosomal structures were also observed in fibroblasts from affected individuals (accumulation of lysosomes and/or presence of highly aberrant compartments with content typical of lysosomal dysfunction). Overall the data presented suggest a critical role for OXR1 in lysosomal biology. Although previous reports suggested that OXR1 is involved in oxidative stress resistance, studies performed by the authors suggested that oxidative stress is probably not the driver of the mutant fly defects. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1129 | PNPT1 |
Konstantinos Varvagiannis changed review comment from: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed. Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available). PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairement due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals. Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported. Overall, this gene might be considered for upgrade to green rating.; to: Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed. Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available). PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals. Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported. Overall, this gene might be considered for upgrade to green rating. |
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| Intellectual disability - microarray and sequencing v2.1102 | DMXL2 |
Konstantinos Varvagiannis changed review comment from: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc). Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited. DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below. OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following: - Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AD) [based on refs 2,3] - ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype] - ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1] DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID. [1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion. ----------- [2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc). ----------- [3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes. All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years. Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3): - Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*) - Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*) - Fam3 (2 sibs) : homozygosity for c.7518-1G>A Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605]. In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot. DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al). The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ). As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872). In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis. shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation. The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy. Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) .; to: This gene can be considered for upgrade to green rating (ID and epilepsy with >=4 relevant individuals/families/variants and >=2 studies, role of the protein, effect of variants in most cases demonstrated, phenotypic similarities with other disorders affecting autophagy, some evidence from animal models, etc). Rare heterozygous variants disrupting DMXL2 (intragenic losses/gains, SNVs, CNVs affecting also additional genes) have been reported in individuals with variable neurodevelopmental disorders (ASD and ID) or psychiatric phenotypes [Costain et al. 2019 - PMID: 30732576 - summarized in Table 1]. (Highly) variable expressivity and possibly incomplete penetrance were proposed in the respective study. As a result evidence for ID/seizures due to monoallelic variants appears to be relatively limited. DD, ID and (probably) epilepsy appear however to be features in several individuals with biallelic pathogenic variants as summarized in the studies below. OMIM recently added a relevant entry with the DMXL2-associated phenotypes being the following: - Epileptic encephalopathy, early infantile, 81; EIEE81 - 618663 (AR) [based on refs 2,3] - ?Deafness, autosomal dominant 71 - 617605 (AD) [DD/ID/seizures are not part of the phenotype] - ?Polyendocrine-polyneuropathy syndrome - 616113 (AR) [based on ref1] DMXL2 is not associated with any phenotype in G2P. In SysID it is listed as a candidate ID gene based on the report by Tata et al (ref1). This gene is included in some gene panels for ID. [1] Tata el al. (2014 - PMID: 25248098) reported on 3 sibs born to consanguineous Senegalese parents, presenting with a progressive endocrine and neurodevelopmental disorder. Features incl. incomplete puberty, central hypothyroidism, abnormal glucose regulation, moderate ID (3/3) and peripheral polyneuropathy. Seizures were not part of the phenotype. Linkage analysis suggested 2 candidate regions on chromosomes 13 and 15 with a LOD score of 2.5. High throughput sequencing of genes within these regions (~500) in an affected member and parent revealed a 15 bp in-frame deletion of DMXL2 (NM_015263.4:c.5827_5841del / p.Asp1943_Ser1947del). Sanger sequencing of other affected and unaffected members supported AR inheritance. RT-qPCR demonstrated that DMXL2 mRNA levels in blood lymphocytes were significantly lower in homozygous patients compared to heterozygous or wt family members or controls. The authors demonstrated that the encoded protein (rabconnectin-3a) is a synaptic protein (expressed in exocytosis vesicles) at the ends of axons of GnRH producing neurons. Neuron-specific deletion of one allele in mice resulted in delayed puberty and very low fertility. Adult mice had lower number of GnRH neurons in hypothalamus. siRNA-mediated downregulation of Dmxl2 expression in an insulin-secreting cell line resulted in only slight insulin secretion in response to augmenting concentrations of glucose, providing evidence of involvement of the protein in control of regulated insulin secretion. ----------- [2] Maddirevula et al. (2019 - PMID: 30237576) reported briefly on a 36 months old boy, born to consanguineous parents, homozygous for a frameshift DMXL2 variant [individual 17-3220 | NM_001174117.1:c.4349_4350insTTACATGA or p.(Glu1450Aspfs*23)]. Features included focal seizures (onset at the age of 3m) with subsequent global DD, absent eye contact, cerebral atrophy and macrocephaly. This individual was identified following re-evaluation of exome data in a database of ~1550 exomes specifically for homozygous variants that would have been classified earlier as LP/P if the respective gene had sufficient evidence for association with a disorder. The family was not reported to have other affected members. As the authors noted, the boy was not known to have the multi-endocrine abnormalities reported by Tata et al. There are no additional information provided (eg. on confirmation of variants, etc). ----------- [3] Esposito et al. (2019 - PMID: 31688942) report on 3 sibling pairs (all 3 families unrelated) with biallelic DMXL2 mutations and summarize previous evidence on the gene and the DMXL2-related phenotypes. All presented a highly similar phenotype of Ohtahara syndrome (seizures with onset in the first days of life, tonic/myoclonic/occasionaly focal, burst-suppression upon EEG), profound DD/ID, quadriparesis, sensorineural hearing loss and presence of dysmorphic features. Sibs from 2 families presented evidence of peripheral polyneuropathy. Early brain MRIs revealed thin CC and hypomyelination in all, with later scans suggestive of gray and white matter shrinkage with leukoencephalopathy. None achieved developmental skills following birth with 5/6 deceased by the age of 9 years. Exome sequencing revealed biallelic DMXL2 variants in all, with compatible parental segregation studies (NM_015263.3): - Fam1 (2 sibs) : c.5135C>T (p.Ala1712Val) in trans with c.4478C>G (p.Ser1493*) - Fam2 (2 sibs) : homozygosity for c.4478C>A (p.Ser1493*) - Fam3 (2 sibs) : homozygosity for c.7518-1G>A Heterozygous parents (aged 39-59) did not exhibit hearing impairment [report of a single multigenerational family by Chen et al (2017 - PMID: 27657680) where a heterozygous missense variant segregated with hearing loss - respective OMIM entry: ?Deafness, autosomal dominant 71 - 617605]. In patients' fibroblasts, effect of the variants on mRNA/protein expression was demonstrated with mRNA expressed only in a patient from family 1, and degraded/absent for the 2 stopgain SNVs affecting codon 1493. Skipping of ex31 leading to frameshift/introduction of a PTC was shown for the splice variant (p.Trp2508Argfs*4 secondary to c.7518-1G>A). Protein was also absent upon western-blot. DMXL2 encodes a vesicular protein, DmX-Like protein 2 or rabconnectin-3a (cited Tata et al). The gene is expressed in brain ( https://www.gtexportal.org/home/gene/DMXL2 ). As Esposito et al comment, it is known to regulate the trafficking and activity of v-ATPase the latter having a role in acidifying intracellular organelles and promoting endosomal maturation (cited PMIDs : 25248098, 19758563, 22875945, 24802872). In line with this, staining of patients' fibroblasts using the acidotropic dye LysoTracker demonstrated increased signal, reversed by re-expression of DMXL2 protein. Overall an acidic shift in pH with impairment of lysosomal structures and function was suggested. The authors provided additional evidence for altered lysosomal function and associated autophagy with accumulation of autophagy receptors (eg p62) and substrates (polyubiquitinated proteins). Vacuolization and accumulation of atypical fusion-like structures was shown upon ultrastractural analysis. shRNA-mediated downregulation/silencing of Dmxl2 in mouse hippocampal neurons resulted also in altered lysosomal structures and defective autophagy. The neurons exhibited impaired neurite elongation and synapse formation. The authors suggest similarities with Vici syndrome, where biallelic EPG5 mutations result in autophagic defects and clinical manifestations of DD/ID/epilepsy. Dmxl2 homozygous ko mice display embryonic lethality with heterozygous mice displaying macrocephaly and corpus callosum dysplasia (cited PMIDs: 25248098, 30735494) . |
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| Intellectual disability - microarray and sequencing v2.1098 | TMX2 |
Konstantinos Varvagiannis gene: TMX2 was added gene: TMX2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMX2 were set to 31586943; 31270415 Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration Penetrance for gene: TMX2 were set to Complete Review for gene: TMX2 was set to AMBER Added comment: PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI. All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones. Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families). Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks. The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals). This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven. TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article. As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging). ------- Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism). ------- There is no associated phenotype in OMIM/G2P/SysID. ------- Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1098 | PCYT2 |
Konstantinos Varvagiannis gene: PCYT2 was added gene: PCYT2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PCYT2 were set to 31637422 Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy Penetrance for gene: PCYT2 were set to Complete Review for gene: PCYT2 was set to GREEN Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations. The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy. Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below): - P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu - P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one. Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID). For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive. All variants were absent from / had extremely low AF in public databases, with no homozygotes. Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway. In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability. Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied: - Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant. - RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls. - Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls. The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping. CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish. Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088). Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life. PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID. As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating. [Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1098 | NTNG2 |
Konstantinos Varvagiannis gene: NTNG2 was added gene: NTNG2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NTNG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NTNG2 were set to 31372774; 31668703 Phenotypes for gene: NTNG2 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Microcephaly; Seizures Penetrance for gene: NTNG2 were set to Complete Review for gene: NTNG2 was set to GREEN Added comment: [1] Abu-Libdeh et al. (2019 - PMID: 31372774) reported 8 individuals from 4 unrelated consanguineous families of Arab Muslim origin, all homozygous for NM_032536.3:c.376dup - p.(Ser126PhefsTer241). Common features included hypotonia, failure to achieve milestones and developmental stagnation without regression during the first year (~9m) of life and severe ID. Minimal purposeful hand use (grasping and bringing objects to mouth), hand stereotypies and bruxism were also observed. Microcephaly and impaired growth were almost universal (with the exception of 2 having an OFC at ~10% percentile). Relevant previous investigations were normal in all and included MECP2, SMN1, aCGH, metabolic testing, etc. The variant was identified by exome in all, and Sanger confirmed with compatible segregation studies in parents and sibs. The variant was found within a shared haplotype of ~4.35 Mb, probably due to a founder effect. [2] Dias et al. (2019 - PMID: 31668703) described 16 individuals from 7 unrelated families from Iran, Mexico, Turkey, Egypt and Bangladesh. Parents were known to be consanguineous or shown to be distantly related. All patients were homozygous for missense variants private to each family (7 variants) identified following exome sequencing. Shared features incl. hypotonia, GDD, severe to profound ID and behavioral anomalies incl. autistic features/stereotypies (most), screaming/laughing spells (most), bruxism. Microcephaly (5/14), growth below average/FTT and GI problems were also observed. Epilepsy was reported in 5 individuals belonging to 4 different families in these 2 studies (5/24 overall / 4 variants). Netrin-G2, the encoded protein, is bound to the plasma membrane by GPI-anchors. Netrins-G2 and G1 (another member of the Netrin-G subfamily) are enriched in presynaptic terminals. Interaction with their cognate Netrin-G ligand trans-synaptic partners / receptors (NGL2, NGL1 respectively) has been shown to promote axon outgrowth, induce and maintain excitatory synapse formation. Complementary and non-overlapping expression in the developping and mature CNS has been shown for Netrin-G2/1 in mice (several references provided by Abu-Libdeh / Dias). Variant effect : The frameshift variant was not studied by Abu-Libdeh et al. Variants in the 2nd ref. were all missense, displayed no-specific localization and were suggested to affect protein stability and/or expression at the cell surface as 4/7 involved loss or addition of cystein residues (possibly creating unpaired cysteins) and 2 of the remaining 3 were predicted to affect the hydrophobic core. In line with this, overexpression of wt/variant constructs in HeLa cells demonstrated substantially decreased cell surface expression for all variants. Mouse models/phenotypes : Dias et al. showed that siRNA-mediated Ntng2 knockdown in N2a cells led to significant reduction in neurite number and length. Studied previously, Ntng2 knockout mice display impaired learning, memory, visual and motor functioning (PMID cited : 26746425). NTNG2 is not associated with any phenotype in OMIM/G2P. SysID lists it among the candidate ID genes, citing PMID: 29302074 (not here reviewed & NTNG2 not in the main text). Overall this gene can be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, consistent phenotype in both reports, role of the gene, in silico and in vitro studies, animal model, etc) or amber. [Please consider inclusion in other panels if relevant eg. ASD panel (many individuals having autistic / Rett-like features or epilepsy) or epilepsy (>3 individuals/families/variants although most families were also consanguineous)] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1098 | IQSEC1 |
Konstantinos Varvagiannis gene: IQSEC1 was added gene: IQSEC1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: IQSEC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IQSEC1 were set to 31607425 Phenotypes for gene: IQSEC1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature Penetrance for gene: IQSEC1 were set to Complete Review for gene: IQSEC1 was set to AMBER Added comment: Ansar et al. (2019 - PMID: 31607425) reported on 5 individuals with biallelic IQSEC1 variants. Common features included hypotonia, DD, speech impairment, severe ID, behavioral problems as well as short stature. Early-onset seizures were observed in 3 sibs (for whom there was also a paternal family history of seizures). These subjects belonging to 2 consanguineous families from Pakistan and S. Arabia were found to harbor homozygous missense variants private to each family (Fam1: NM_001134382.2:c.1028C>T or p.Thr354Met following SNP genotyping of several members and exome of the proband | Fam2: c.962G>A or p.Arg321Gln following exome in 2 affected members). Sanger confirmation and study of parents (+/- sibs) were compatible. The homozygous variant was the only candidate in the 1st family (also following exclusion of other causes of ID/short stature), and most likely/compatible with the patient's phenotype in the 2nd. As the authors note, IQSEC1-3 encode guanine exchange factors (GEFs) for the ARF family of GTPases. IQSEC2 is a known XLID gene, while biallelic IQSEC3 mutations in ID have been recently reported (PMID: 31130284), all presenting phenotypic similarities (ID, short stature, speech defect). Previous studies cited had shown that IQSEC1 & 2 are concentrated at the postsynaptic density of glutamatergic synapses in mammalian brain, playing a role in actin-dependent processes incl. AMPA receptor trafficing at synapses (all refs in article). Drosophila model: The ortholog of IQSEC1, 2 and 3 is schizo and the phenotype associated with its loss is a growth cone guidance defect through dysregulation of the Slit-Robo pathway (all refs in article). The authors studied overexpression of either reference IQSEC1 cDNA or variant cDNAs in wt flies, the former only being toxic/lethal. Loss of schizo was also embryonically lethal but was partially rescued by expression of reference IQSEC1 cDNA. Expression of cDNA for the 2 variants did not rescue lethality. As a result LoF appears to be the underlying effect of both variants. The authors provided evidence that schizo is localized in glia and neurons at various stages of development and is important for proper axon guidance in both CNS and PNS. In Drosophila, schizo is also localized in photoreceptors and RNAi-mediated knockdown resulted in severely impaired sight (also observed in 1 patient). Mouse model: Through generation of Iqsec1-floxed mice, it was demonstrated that targeted depletion of Iqsec1 in the cortex resulted in increased density/immature morphology of dendritic spines. IQSEC1 is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in gene panels for ID. As a result, this gene could be considered for inclusion in the ID panel as probably as amber (2 families/variants). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1062 | TDP2 |
Konstantinos Varvagiannis gene: TDP2 was added gene: TDP2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TDP2 were set to 24658003; 30109272; 31410782 Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949) Penetrance for gene: TDP2 were set to unknown Review for gene: TDP2 was set to GREEN gene: TDP2 was marked as current diagnostic Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder. TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity. The gene is expressed in fetal and adult human brain. Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role. Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes. Published studies are summarized below. TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID. Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model). ------------ [1] - PMID: 24658003 (Gómez-Herreros et al. 2014): Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3). A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study). The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity). The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject. As also commented: - TDP2 has relevant expression in human (particularly adult) brain. - Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated. - Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968). [2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018): A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle). [3] - PMID: 31410782 (Ciaccio et al. 2019): A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.1062 | APC2 |
Konstantinos Varvagiannis gene: APC2 was added gene: APC2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669 Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system Penetrance for gene: APC2 were set to Complete Review for gene: APC2 was set to GREEN gene: APC2 was marked as current diagnostic Added comment: Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported. ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles). In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out. APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS. All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations. Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer. Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2. Relevant articles: PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model] PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model] PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families] ----- In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. In SysID, APC2 belongs to the Current primary ID genes. APC2 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc, GeneDx). ----- Overall, this gene could be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, highly specific pattern of lissencephaly in 12/14, mouse model supporting migration defects and impaired learning/memory) rather than amber (differences between the 1st and the other families reported as for the OFC and presence of lissencephaly). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1046 | PMPCB |
Konstantinos Varvagiannis changed review comment from: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954). 5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218). Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset. Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2): - c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B] - c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C] - c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs] The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel). Extensive studies demonstrated (perhaps a better summary provided by OMIM): - Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells. - Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity. - Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters. - Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue. Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested). PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable). As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen; to: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954). 5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218). Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset. Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2): - c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B] - c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C] - c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs] The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel). Extensive studies demonstrated (perhaps a better summary provided by OMIM): - Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells. - Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity. - Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yeast strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters. - Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue. Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested). PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable). As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.1046 | PMPCB |
Konstantinos Varvagiannis gene: PMPCB was added gene: PMPCB was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: PMPCB was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: PMPCB were set to Multiple mitochondrial dysfunctions syndrome 6, 617954 Penetrance for gene: PMPCB were set to Complete Review for gene: PMPCB was set to GREEN gene: PMPCB was marked as current diagnostic Added comment: Biallelic pathogenic PMPCB variants cause, Multiple mitochondrial dysfunctions syndrome 6 (MIM 617954). 5 relevant individuals from 4 unrelated families (in one case consanguineous) have been reported by Vögtle et al. (2018 - PMID: 29576218). Onset of symptoms (eg. hypotonia) often preceded a period of developmental regression/stagnation which was common in all individuals and occurred within the first 2 years of life, usually following febrile illness. In all cases neurological features were severe (lack of ambulation/speech). Seizures were observed in 4 individuals from 3 families, with onset at the age of 11-24m. MRI images demonstrated T2 signal hyperintensities of the basal ganglia with cerebellar and cerebral atrophy in some. Deterioration with early death was reported on three occasions, though some years after symptom onset. Following exclusion of other diagnoses in some cases (eg. aCGH, epilepsy panel), WES identified biallelic PMPCB missense variants, supported by Sanger confirmation and segregation studies. The following variants were reported (NM_004279.2): - c.523C>T (p.Arg175Cys) in trans with c.601G>C (p.Ala201Pro) [Fam A and B] - c.524G>A (p.Arg175His) in trans with c.530T>G (p.Val177Gly) [Fam C] - c.1265T>C (p.Ile422Thr) in homozygous state [Fam D with 2 affected sibs] The gene encodes the catalytic (beta) subunit of the mitochondrial processing protease (MPP) which is responsible for the cleavage/maturation of nuclear-encoded mitochondrial precursor proteins after their import in mitochondria. The alpha subunit is encoded by PMPCA (green rating proposed for this panel). Extensive studies demonstrated (perhaps a better summary provided by OMIM): - Reduced PMPCB protein levels in mitochondria isolated from patient fibroblasts or patient-derived pluripotent stem cells. - Frataxin maturation was impaired with accumulation of the intermediate form and lower amounts of mature FXN, indicating decrease in MPP activity. - Analysis of the homologous Mas1 S. cerevisiae mutants was carried out, with the exception of Ile422Thr (corresponding to Mas1 - Ile398Thr), the introduction of which did not yield viable yiest strains. Homologous mutations led to a temperature-sensitive phenotype with accumulation of immature/unprocessed precursor proteins and decrease of mature/processed forms both in vivo or in organello (following isolation of mitochondria). Under conditions of heat stress, Mas1 mutations decreased biogenesis of Fe-S clusters. - Respiratory chain complexes I-III contain Fe-S clusters. In muscle biopsy from an affected individual, complex II activity was significantly reduced (although this was not the case in fibroblasts or liver biopsy). Dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes (eg. aconitase) was also shown in muscle tissue. Regression/stagnation with seizures/non-achievement of milestones may justify testing for an ID / epilepsy gene panel. In addition, metabolic studies or mitochondrial respiratory chain complex studies were sometimes non-informative (lactate elevated in 3/5 subjects) or not carried out at all / in relevant tissues (muscle biopsy in 2 individuals, fibroblasts/liver biopsy did not demonstrate reduced complex activity when tested). PMPCB is included in the ID gene panel of Radboudumc, as well as the SysID database. The gene is included in the DD panel of G2P associated with "Neurodegeneration in Early Childhood" (disease confidence : probable). As a result, PMPCB can be considered for inclusion in both epilepsy and ID panels as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.1015 | GOT2 |
Konstantinos Varvagiannis gene: GOT2 was added gene: GOT2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: GOT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GOT2 were set to 31422819 Phenotypes for gene: GOT2 were set to Global developmental delay; Intellectual disability; Seizures; Increased serum lactate; Hyperammonemia; Microcephaly; Failure to thrive; Feeding difficulties; Abnormality of nervous system morphology Penetrance for gene: GOT2 were set to Complete Review for gene: GOT2 was set to GREEN Added comment: van Karnebeek et al. (2019 - PMID: 31422819) report on 4 individuals from 3 families, with biallelic GOT2 pathogenic variants (3 missense SNVs and 1 in-frame deletion). The phenotype corresponded to a metabolic encephalopathy with onset of epilepsy in the first year of life (4/4) with DD and ID (4/4). Additional features included postnatal microcephaly, failure to thrive/feeding difficulties and cerebral anomalies (atrophy and white matter). All subjects had high blood lactate and hyperammonemia. Plasma serine was low in one case (alternative causes were ruled out). Administration of serine and pyridoxine led to clinical improvement (cessation / better control of seizures) in 2 subjects suggesting that GOT2 deficiency may be amenable to therapeutic intervention. [Treatment could not be started in the 2 further affected individuals]. GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase, a component of the malate-aspartate shuttle (MAS). The latter is important for intracellular NAD(H) redox homeostasis. The authors provide several lines of evidence that GOT2 deficiency explains the patients' phenotype and metabolic defects incl. : - Reduced GOT2 protein levels (due to lower expression/impaired stability) and diminished activity in patient fibroblasts (lower activity was also shown for carriers). Rescue of the GOT enzymatic activity was observed upon transduction of patient fibroblasts using lentiviral particles with wt GOT2. - Impairment of de novo serine biosynthesis in patient (and to a lesser extent in carrier) fibroblasts compared to controls. This was similar in GOT2-knockout HEK293 cells. Serine biosynthesis in these cells was restored by pyruvate supplementation. - CRISPR/Cas9 Got2-knockout mice resulted in early lethality (during pregnancy). Heterozygous mice were viable and healthy. - Morpholino knockdown of got2a in zebrafish was shown to perturb embryonic development (smaller head, slow circulation, bend body, brain developmental defects, etc). Pyridoxine and serine in embryo water resulted in milder phenotypes/improved morphant survival. Zebrafish got2a morphants had seizure-like spikes upon EEG that were rescued by treatment with pyridoxine. GOT2 is not associated with any phenotype in OMIM/G2P. As a result, this gene can be considered for inclusion in both epilepsy and ID gene panels probably as green (3 families, relevant phenotypes and severity, evidence from cell and animal studies) or amber. [Please consider inclusion in other relevant panels eg. mitochondrial disorders, metabolic disorders and/or addition of the 'treatable' tag]. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1015 | DDX6 |
Konstantinos Varvagiannis gene: DDX6 was added gene: DDX6 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DDX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DDX6 were set to 31422817 Phenotypes for gene: DDX6 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Unsteady gait; Abnormality of the cardiovascular system; Abnormality of the genitourinary system; Abnormality of limbs Penetrance for gene: DDX6 were set to unknown Review for gene: DDX6 was set to GREEN Added comment: Balak et al. (2019 - PMID: 31422817) report on 5 individuals with de novo likely pathogenic DDX6 variants. Clinical details are provided for 4. Frequent features included hypotonia, DD, ID (4/4), gait instability, cardiac, genitourinary as well anomalies of the extremities. DDX6 belongs to the DEAD box family of RNA helicases. This helicase is an essential component of processing bodies (P-bodies / PBs), which are mebrane-less organelles involved in storage of mRNAs and proteins related to mRNA decay thus playing an important role in translational repression/post-transcriptional regulation (PMID: 29381060). All 5 variants had occurred as de novo events, clustered in exon 11 (NM_004397.5) and affected residues 372-373 of the QxxR motif (c.1115A>G or p.His372Arg / c.1118G>A or p.Arg373Gln) or 390-391 of the V motif (c.1168T>C or p.Cys390Arg / c.1171A>C or p.Thr391Pro / c.1172C>T or p.Thr391Ile). The specific motifs (and RecA-2 domain) are involved in RNA binding, helicase activity and protein-partner binding. Fibroblasts from 2 individuals were studied. Patient cells contained fewer PBs compared to cells from relatives/control-subjects, despite similar amounts of DDX6 protein upon immunobloting. Additional studies suggested that DDX6 variants caused impaired binding of other DDX6 protein partners involved in PB formation / translation repression (eg. LSM14A, 4E-T, etc) thus resulting in defective PB assembly. Transcriptome analysis in fibroblasts from one affected individual revealed (significant) differential expression of >1000 genes, enriched for genes related to protein translation, ribosome and RNA processing. As the authors discuss, given the residual PB assembly, haploinsufficiency is favored over a dominant-negative effect which would result in complete suppression of PBs (as sugested by a previous study of a dominant-negative DDX6 variant - PMID cited: 19297524). [In gnomAD, DDX6 has a Z-score for missense variants of 3.78 and a pLI of 1]. DDX6 is not associated with any phenotype in OMIM. In G2P it is associated with ID (disease confidence : probable / mutations : all missense/in frame). As a result, this gene can be considered for inclusion in the ID panel as green (sufficient cases, relevant phenotype, functional studies) or amber. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.996 | POLR2A |
Konstantinos Varvagiannis gene: POLR2A was added gene: POLR2A was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: POLR2A were set to 31353023 Phenotypes for gene: POLR2A were set to Generalized hypotonia; Global developmental delay; Feeding difficulties Penetrance for gene: POLR2A were set to unknown Review for gene: POLR2A was set to GREEN gene: POLR2A was marked as current diagnostic Added comment: Haijes et al. (2019 - PMID: 31353023) report on 16 individuals with heterozygous de novo POLR2A variants. DD in all domains was observed in all individuals, ranging from mild to severe (in 8/16 moderate or more severe). The developmental scores were stable over time (as for eventual catch-up/decline) supporting relevance to the current panel. POLR2A encodes RPB1, the largest subunit of RNA polymerase II (pol II). Pol II is responsible for the transcription of all protein coding genes as well as several long/short non-coding RNA genes. Missense, in-frame deletions as well as truncating mutations were observed. POLR2A has a pLI of 1 and a Z-score for missense variants of 7.13 (one of the highest ones). The reported variants did not cluster in specific domains of the protein although many were in regions relatively depleted in benign variants in gnomAD (stretches of desert Z-scores). Measures such as the CADD scores did not discriminate between deleterious ones and those in gnomAD. Different layers of structural analyses, functional analyses (impaired growth in S. cerevisiae in genetic background lacking transcr. factors Dst1 / Sub1 - suggesting reduced transcriptional fidelity / reduced HeLa cell viability) or phenotypic overlap were used to classify variants in probably disease causing (11), possibly disease causing (4 - only based on phenotypic overlap) or of unknown effect (1 variant - due to unavailable/incomplete phenotype). Some variants were predicted to act by haploinsufficiency while others (missense ones) by a dominant-negative mechanism, the latter being more likely to result in severe phenotypes. Mutations in genes encoding subunits of pol III (responsible for tRNA synthesis) are associated with leukodystrophy phenotypes with some limited overlap with POLR2A (delayed myelination/white-matter loss/tooth misalignment). Mutations in genes encoding other subunits of pol II (other than RPB1 encoded by POLR2A) have not been implicated in disease though. POLR2A is not associated with any phenotype in OMIM/G2P. This gene is included in panels for ID offered by some diagnostic laboratories [eg. Utrecht UMC - affiliation of many co-authors of this study or GeneDx]. As a result, this gene can be considered for inclusion in the ID panel probably as green, or amber. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.996 | AFF3 |
Konstantinos Varvagiannis changed review comment from: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence. The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy]. 9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13. AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development. Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot. Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study]. Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects. Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant. Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3. ---- In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM. Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel). ---- As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article).; to: Voisin et al. (2019 - https://doi.org/10.1101/693937) report on 10 individuals with de novo missense AFF3 variants affecting a 9-amino-acid sequence (degron) important for the protein's degradation and summarize the phenotype of an additional individual previously described by Steichen-Gersdorf et al. (2008 - PMID: 18616733) with a 500 kb affecting only AFF3 (LAF4) and removing also this sequence. The phenotype of missense variants consisted of kidney anomalies, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary problems and was overlapping with that of the deletion. [10 of 11 subjects exhibited severe developmental epileptic encephalopathy]. 9 probands harbored missense variants affecting the codon 258 while one individual had a variant affecting codon 260 [c.772G>T or p.Ala258Ser (x2), c.772G>A or p.Ala258Thr (x6), c.773C>T or p.Ala258Val (x1) and c.779T>G or p.(Val260Gly) (x1) - NM_001025108.1 / NP_001020279.1]. The deletion removed exons 4-13. AFF1-4 are ALF transcription factor paralogs, components of the transcriptional super elongation complex regulating expression of genes involved in neurogenesis and development. Using HEK293T cells expressing FLAG-tagged AFF3 (and AFF4) wt or mutants, accumulation of mutated forms was shown upon immunoblot. Aff3+/- and/or -/- mice exhibit skeletal defects. These were more pronounced in homozygous mice which demonstrated also some elements in favor of kidney dysfunction and/or metabolic deregulation and possible neurological dysfunction (signs of impaired hearing and diminished grip strength). Homozygous mice had CNS anomalies (enlarged lateral ventricles and decreased corpus callosum size) similar to some affected individuals, although these were not observed in another Aff3-/- model. Knock-in mice modeling the microdeletion and the Ala258Thr variant displayed lower mesomelic limb deformities and early lethality respectively [cited PMIDs : 21677750, 25660031, knock-in model was part of the present study]. Accumulation of the protein in zebrafish (by overexpression of the human wt AFF3 mRNA), led to morphological defects. Reanalysis of transcriptome data from previously generated HEK293T cell lines knocked down for AFF2, AFF3 and AFF4 by shRNAs (study) suggested that these transcription factors are not redundant. Finally, CHOPS syndrome (#616368) due to mutations of AFF4 also leading to increased protein stability presents a partially overlapping phenotype (incl. cognitive impairment) to that of AFF3. ---- Shimizu et al. (8/2019 - PMID: 31388108) describe an additional individual with de novo AFF3 missense variant. The phenotype overlaps with that summarized by Voisin et al. incl. mesomelic dysplasia with additional skeletal anomalies, bilateral kidney hypoplasia and severe DD at the age of 2.5 years. Seizures and pulmonary problems were not observed. Although a different RefSeq is used the variant is among those also reported by Voisin et al. [NM_002285.2:c.697G>A (p.Ala233Thr) corresponding to NM_001025108.1:c.772G>A (p.Ala258Thr)]. ---- In G2P, AFF3 is associated with Skeletal dysplasia with severe neurological disease (disease confidence : probable / ID and seizures among the assigned phenotypes). There is no associated phenotype in OMIM. Some diagnostic laboratories include AFF3 in their ID panel (eg. among the many co-authors' affiliations GeneDx and Victorian Clinical Genetics - which was already listed as source for AFF3 in the current panel). ---- As a result this gene can be considered for upgrade to green (relevant phenotype and severity, sufficient cases, evidence for accumulation similar to AFF4, animal models, etc) or amber (pending publication of the article). [Review modified to add additional reference/case report] |
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| Intellectual disability - microarray and sequencing v2.978 | ZNF142 |
Catherine Snow Source Expert Review Green was added to ZNF142. Source Expert Review was added to ZNF142. Added phenotypes Neurodevelopmental disorder with impaired speech and hyperkinetic movements, 618425 for gene: ZNF142 Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v2.978 | CUX1 |
Catherine Snow Source Expert Review Green was added to CUX1. Source Expert Review was added to CUX1. Added phenotypes Global developmental delay with or without impaired intellectual development, 618330 for gene: CUX1 Publications for gene CUX1 were changed from 30014507; 20510857; 25059644 to 25059644; 20510857; 30014507 Rating Changed from No List (delete) to Green List (high evidence) |
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| Intellectual disability - microarray and sequencing v2.953 | DEGS1 |
Konstantinos Varvagiannis gene: DEGS1 was added gene: DEGS1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DEGS1 were set to 30620337; 30620338; 31186544 Phenotypes for gene: DEGS1 were set to Leukodystrophy hypomyelinating 18, MIM 618404) Penetrance for gene: DEGS1 were set to Complete Review for gene: DEGS1 was set to GREEN Added comment: Several individuals with biallelic pathogenic DEGS1 variants have been reported to date, in the following studies : [1] Pant et al. 2019 (PMID: 30620337) : 19 patients from 13 unrelated families [2] Karsai et al. 2019 (PMID: 30620338) : 1 individual [3] Dolgin et al. 2019 (PMID: 31186544) : 4 individuals belonging to a large consanguineous kindred As summarized in the first article and OMIM, affected individuals may have very poor psychomotor development, dystonia, spasticity, seizures with hypomyelinating leukodystrophy upon brain imaging and/or progressive atrophy of corpus callosum, thalami and cerebellum. Although a severe form overall was reported for many individuals in the first study, variable severity (eg. mild to severe ID) was reported among individuals belonging to the same kindred in the report by Dolgin et al. DEGS1 encodes Δ4-dehydroceramide desaturase which catalyzes conversion of dihydroceramide (DhCer) to ceramide (Cer) in the de novo ceramide biosynthetic pathway. Ceramide is the central unit of all sphingolipids, which are components of cellular membranes and play key roles in several processes incl. cell differentiation, neuronal signaling and myelin sheath formation. Sphingolipid balance is important for the CNS as demonstrated in the case of lysosomal disorders (eg. Gaucher, Niemann Pick, Farber) one enzymatic step away from DEGS1. Variants of all types (missense, stopgain, frameshift) have been reported with the majority/almost all located in the fatty acid desaturase (FAD) domain. Extensive studies have been carried out and demonstrated: - impaired DEGS1 activity in patients' fibroblasts and muscle suggested by increased DhCer/Cer ratio and compatible broader biochemical effects (higher levels of dihydrosphingosine, dihydrosphingomyelins, etc. and lower levels of sphingosine, monohexosylceramides, etc). - increased ROS production in patient fibroblasts (similar to a Drosophila model of excess DhCer), - high expression of the gene in child and adult CNS tissues from control individuals (evaluated by RT-qPCR in Ref. 1). A previous study has suggested that DEGS1 expression is upregulated during the 4-9th week of human embryogenesis (PMID cited: 20430792) which may suggest an important role for neural system development. - decreased expression for some variants either evaluated at the mRNA (RT-qPCR) / protein level (by Western Blot) - In zebrafish loss of Degs1 resulted in increased DhCer/Cer ratio, locomotor disability and impaired myelination similar to the patients' phenotype. Fingolimod, a sphingosine analog inhibiting Cer synthase (one step prior to DEGS1 in the de novo ceramide biosynthesis pathway, and converting sphingosine to ceramide in the salvage pathway) reduced the DhCer/Cer imbalance, ameliorated the locomotor phenotype and increased the number of myelinating oligodendrocytes in zebrafish, while it reduced the ROS levels in patient fibroblasts. Previous animal models: Apart from the zebrafish model (Pant et al.), higher DhCer/Cer ratios have been shown in homozygous Degs1 -/- mice similar to what is also observed in D. melanogaster. As summarized in MGI (and the previous studies as well) "mice homozygous for a knock-out allele exhibit premature death, decreased to absent ceramide levels, decreased body weight, scaly skin, sparse hair, tremors, hematological and blood chemistry abnormalities, decreased bone mineral content and density and decreased liver function." (PMIDs cited: 17339025, 28507162). ---- The respective OMIM entry is Leukodystrophy, hypomyelinating, 18 (#618404). DEGS1 is not associated with any phenotype in G2P. ---- As a result, DEGS1 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, sufficient number of individuals, supportive expression and biochemical studies, animal models, etc). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.951 | POU3F3 |
Konstantinos Varvagiannis gene: POU3F3 was added gene: POU3F3 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: POU3F3 were set to https://doi.org/10.1016/j.ajhg.2019.06.007; 24550763 Phenotypes for gene: POU3F3 were set to Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior Penetrance for gene: POU3F3 were set to unknown Review for gene: POU3F3 was set to GREEN gene: POU3F3 was marked as current diagnostic Added comment: Snijders Blok et al. (2019, DOI: https://doi.org/10.1016/j.ajhg.2019.06.007) report on 19 individuals with heterozygous POU3F3 variants. Features included hypotonia in some, DD/ID (19/19) with impairment in speech and language skills, and autism-like symptoms with formal ASD diagnosis in 7(/19). Epilepsy was reported for 2 individuals. Overlapping facial features were noted among these individuals. POU3F3 encodes a member of the class III POU family of transcription factors expressed in the central nervous system (Sumiyama et al. 1996, PMID: 8703082 cited in OMIM) and as the authors comment holds a role in regulation of key processes, eg. cortical neuronal migration, upper-layer specification and production and neurogenesis (PMIDs cited: 11859196, 12130536, 22892427, 17141158). In almost all subjects (17/19) the variant had occurred as a de novo event, while one individual had inherited the variant from a similarly affected parent. In total 12 nonsense/frameshift variants, 5 missense ones as well as 1 in-frame deletion were identified following (mostly) trio exome sequencing. All variants were absent from gnomAD, with in silico predictions in favour of pathogenicity. The few missense variants and the in-frame deletion were found either in the POU-specific (NM_006236.2:c.1085G>T / p.Arg362Leu found in 2 subjects) or the POU-homeobox domain (where 2 variants affected the same residue, namely p.Arg407Gly/Leu, the other variant was p.Asn456Ser). POU3F3 is an intronless gene and as a result truncating variants are not subject to NMD. The gene appears to be intolerant to LoF variants (pLI of 0.89 in gnomAD). Western blot analysis of YFP-tagged POU3F3 variants (in HEK293 cell lysates) showed that the YFP-fusion proteins were expressed and had the expected molecular weights. For several truncating variants tested as well as the in-frame deletion, aberrant subcellular localization pattern was demonstrated although this was not the case for 4 missense variants. In vitro studies were carried out and suggested that POU3F3, as is known to be the case for POU3F2, is able to activate an intronic binding site in FOXP2. Using a luciferase assay, transcriptional activation was severely impaired for truncating variants tested, significantly lower for many missense ones with the exception of those affecting Arg407 in which case luciferase expression was either similar to wt (for Arg407Gly) or even increased in the case of Arg407Leu. As the authors comment, both loss- and gain- of function mechanisms may underly pathogenicity of variants. The ability of mutant proteins to form dimers either with wt or themselves was tested. Dimerization capacity was intact for most missense variants but was lost/decreased for truncating variants. The in-frame deletion resulted in impaired dimerization with wt, although homo-dimerization was found to be normal. --- Dheedene et al. (2014 - PMID: 24550763) had previously reported on a boy with ID. aCGH had demonstrated a de novo 360-kb deletion of 2q12.1 spanning only POU3F3 and MRPS9 the latter encoding a mitochondrial ribosomal protein (which would be most compatible with a - yet undescribed - recessive inheritance pattern / disorder). --- POU3F3 is not associated with any phenotype in OMIM/G2P. The gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc, among the principal authors of the study). --- As a result POU3F3 seems to fulfill criteria for inclusion in the current panel probably as green [DD/ID was a universal feature - severity of ID was relevant in 5/10 individuals for whom details were available, functional evidence provided] or amber. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.917 | PPP1R15B | Ivone Leong Phenotypes for gene: PPP1R15B were changed from Microcephaly, short stature, and impaired glucose metabolism 2 to Microcephaly, short stature, and impaired glucose metabolism 2, 616817 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.853 | AP2M1 |
Konstantinos Varvagiannis gene: AP2M1 was added gene: AP2M1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: AP2M1 were set to 31104773 Phenotypes for gene: AP2M1 were set to Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Ataxia; Autistic behavior Penetrance for gene: AP2M1 were set to Complete Review for gene: AP2M1 was set to GREEN Added comment: Helbig et al. (2019 - PMID: 31104773) report on 4 individuals with developmental and epileptic encephalopathy due to a recurrent de novo AP2M1 missense variant (NM_004068.3:c.508C>T or p.Arg170Trp). Seizure types included atonic, myoclonic-atonic, absence seizures (with or without eyelid myoclonia), tonic-clonic etc. Hypotonia, developmental delay (prior to the onset of seizures at 1y 3m to 4y) and intellectual disability were observed in all four. Other features included ataxia (3/4) or autism spectrum disorder (2/4). AP2M1 encodes the μ-subunit of the adaptor protein complex 2 (AP-2). AP2M1 is highly expressed in the CNS. The AP-2 complex is involved in clathrin-mediated endocytosis at the plasma mebrane of neurons and non-neuronal cells. This mechanism is important for recycling synaptic vesicle components at mammalian central synapses. Previous evidence suggests regulation of GABA and/or glutamate receptors at the neuronal surface by AP-2 (several references provided by Helbig et al.). The authors provide evidence for impaired (reduced) clathrin-mediated endocytosis of transferrin in AP-2μ-depleted human HeLa cells upon plasmid-based re-expression of the Arg170Trp variant compaired to re-expression of WT. A similar defect was demonstrated upon comparison of the same process when WT and Arg170Trp re-expression was studied in primary astrocytes from conditional AP-2μ knockout mice. Expression levels, protein stability, membrane recruitment and localization of the AP-2 complex in clathrin-coated pits were similar for the Arg170Trp variant and WT. As a result, the effect of the specific variant is suggested to be mediated by alteration of the AP-2 complex function (/impaired recognition of cargo membrane proteins) rather than haploinsufficiency. AP2M1 is highly intolerant to missense / LoF variants with z-score and pLI in ExAC of 5.82 and 0.99 respectively. As the authors discuss, heterozygous Ap2m1 mutant mice do not have an apparent phenotype. Homozygous mutant mice die before day 3.5 postcoitus, suggesting a critical role in early embryonic development (PMID 16227583 cited) AP2M1 is currently not associated with any phenotype in OMIM / G2P. As a result, this gene can be considered for inclusion in the epilepsy and ID panels probably as green (4 individuals with highly similar phenotype of DEE, relevance of phenotype and/or degree of ID, functional studies, etc) rather than amber (single recurrent variant - although this is also the case for other genes rated green). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.847 | DOCK3 | Rebecca Foulger Phenotypes for gene: DOCK3 were changed from to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.800 | ZNF142 |
Konstantinos Varvagiannis gene: ZNF142 was added gene: ZNF142 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZNF142 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF142 were set to 31036918 Phenotypes for gene: ZNF142 were set to Global developmental delay; Intellectual disability; Seizures; Tremor; Dystonia Penetrance for gene: ZNF142 were set to unknown Review for gene: ZNF142 was set to GREEN Added comment: Khan et al. (2019 - PMID: 31036918) describe the phenotype of 7 females from 4 families, harboring biallelic likely pathogenic ZNF142 variants. Overlapping features included cognitive impairment (ID in 6/7 from 3 families, borderline intellectual functioning was reported one occasion), speech impairement and motor impairment (7/7), and variably penetrant seizures (5/7), tremor (4/7) and dystonia (3/7). Most individuals (5/7) had experienced at least one episode of seizures (tonic-clonic) though seizures were recurrent in 3 sibs. Other disorders with ID (eg. Angelman syndrome, Rett syndrome, chromosomal disorders) or movement disorders as a feature were previously ruled out for many subjects. 6 individuals were homozygous or compound heterozygous for LoF (stopgain or frameshift) variants. One individual harbored 2 missense SNVs in the compound heterozygous state. Variants reported include (NM_001105537.2): c. 817_818delAA (p.Lys273Glufs*32), c.1292delG (p.Cys431Leufs*11), c.3175C>T (p.Arg1059*), c.4183delC (p.Leu1395*), c.3698G>T (p.Cys1233Phe), c.4498C>T (p.Arg1500Trp) with the LoF variants predicted to result in NMD. Expression or functional studies were not carried out. ZNF142 encodes a C2H2 domain-containing transcription factor. Mutations in other zinc finger proteins (ZNF/zfp) have been reported in several neurodevelopmental disorders impacting the CNS (eg. ZBTB20 and ZBTB11 heterozygous and biallelic mutations, respectively) and/or presenting with movement disorders among their manifestations (eg. YY1). As the authors comment, homozygous ablation of the orthologous (Zfp142) locus in mice results in behavioral and neurological phenotypes [MGI ref.ID: J:211773 cited - http://www.informatics.jax.org/marker/reference/J:211773 (though Zfp142 or its locus do not seem to appear in the list)]. ZNF142 is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. It is not associated with any phenotype in OMIM, nor in G2P. As a result, this gene can be considered for inclusion in the current panel as probably as green (individuals from 3 families, appropriate degree of ID for the current panel) or amber (if further evidence would be required). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.800 | SNAP25 |
Konstantinos Varvagiannis gene: SNAP25 was added gene: SNAP25 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006 Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330 Penetrance for gene: SNAP25 were set to Complete Review for gene: SNAP25 was set to GREEN gene: SNAP25 was marked as current diagnostic Added comment: Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below): - Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent. - DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants. - Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant - Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant - Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant - Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported). Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified). SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID. SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.). Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988]. Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants. Animal models discussed: - Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238). - In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548). - Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108). - Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335). In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable). This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). SNAP25 is among the genes discussed by Erger et al. (PMID: 30914295) as associated with ID in OMIM/HPO/G2P/SysID but not included in the current panel. As a result SNAP25 can be considered for inclusion in the ID panel probably as green (3 individuals with ID, role of SNARES in "synaptopathies", supportive animal models) or amber (if functional studies for individual variants would be required). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.800 | CACNA1B |
Konstantinos Varvagiannis gene: CACNA1B was added gene: CACNA1B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CACNA1B was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CACNA1B were set to Global developmental delay; Developmental regression; Seizures; Intellectual disability; Abnormality of movement Penetrance for gene: CACNA1B were set to Complete Review for gene: CACNA1B was set to GREEN Added comment: Gorman et al. (2019 - doi.org/10.1016/j.ajhg.2019.03.005) report on 6 individuals from 3 unrelated families, with biallelic LoF CACNA1B variants. The phenotype corresponds to a developmental epilepic encephalopathy with hyperkinetic movement disorder (ID was a universal feature, DD and/or regression occurred prior to the onset of seizures in several individuals) . CACNA1B encodes calcium channel, voltage-dependent N type, α-1B subunit (Ca v2.2). As commented by the authors, Ca v2.1 and v2.2 are important for SNARE-mediated release of neurotransmitters through modulation of Ca+2 levels. In addition, Ca v2.2 has been postulated to have a role in synaptic plasticity, synaptogenesis, migration of immature neurons, etc. It is thought to have a crucial role in neurotransmission in the early postnatal period (Ca v2.2 channels are subsequently replaced by Ca v2.1 in mature synapses within the thalamus, cerebellum and auditory brainstem). Knockout mice display neurodevelopmental abnormalities including impaired locomotor activity and memory impairment (all ref. cited within the article). 3 sibs, born to 1st cousin parents, harbored p.Leu1222Argfs*29 (NM_000718.4:c.3665del) in the homozygous state. One additional individual was homozygous for p.Arg383*. Compound heterozygosity for a frameshift and a splicing variant (p,Gly1192Cysfs* and c.4857+1G>C) was identified in 2 sibs from a 3rd family. Expression/functional studies have not been performed for any of the variants reported. In OMIM, monoallelic CACNA1B pathogenic variants are associated with ?Dystonia 23 (MIM 614860) based on the identification of a heterozygous missense (R1389H) mutation in members of a Dutch with myoclonus-dystonia syndrome (Groen et al. 2015 - PMID: 25296916). As a result, this gene can be considered for inclusion in the epilepsy and ID panels as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.800 | DOCK3 | Konstantinos Varvagiannis reviewed gene: DOCK3: Rating: AMBER; Mode of pathogenicity: None; Publications: 30976111, 28195318, 29130632; Phenotypes: Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.787 | CDK8 |
Konstantinos Varvagiannis commented on gene: CDK8: Calpena et al. (2019 - PMID: 30905399 - DDD study among the co-authors) report on 12 unrelated individuals with pathogenic CDK8 missense variants. Common features included hypotonia and DD (universal feature). Older children displayed variable degrees of ID (2 mild, 5 moderate, 2 moderate-severe). Other features included feeding difficulties, behavioral disorders, CHD, epilepsy (2 individuals), impaired vision and hearing problems in few. CDK8 (alternatively CDK19) serves a one of the four subunits of a kinase module that reversibly binds to the mediator complex to regulate its activity (in turn, regulation of transcription). Mutations in other genes coding for the 3 other subunits of the kinase module (eg. MED12 or MED13L) lead to syndromic neurodevelopmental disorders. 8 missense CDK8 variants were reported in total. Ser62Leu (NM_001260.2:c.185C>T) was recurrent, observed in 5 subjects. The variants had occurred as de novo events in all cases (10 individuals) where parental samples were available. All variants clustered in the kinase domain (residues 21-335 - of 464 total) around the ATP binding pocket. A thermal stability assay did not reveal gross protein instability in the presence or absence of ATP while the ability to bind ATP was retained for most/all variants. Study of STAT1 phosphorylation was suggestive of attenuated kinase activity for all variants, though to a lesser degree for 2 of them. Given the type of variants (all missense) and the pLI of 0.38 haploinsufficiency appears to be unlikely. A dominant-negative mechanism is favoured. CDK8 is not associated with any phenotype in G2P. As a result, CDK8 can be considered for upgrade to green or amber (if the degree of ID is relevant for the current panel). |
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| Intellectual disability - microarray and sequencing v2.742 | WARS2 |
Konstantinos Varvagiannis gene: WARS2 was added gene: WARS2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: WARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WARS2 were set to 28236339; 28650581; 28905505; 29783990; 29120065 Phenotypes for gene: WARS2 were set to Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710 Penetrance for gene: WARS2 were set to unknown Review for gene: WARS2 was set to GREEN gene: WARS2 was marked as current diagnostic Added comment: Several individuals with biallelic pathogenic WARS2 variants have been published to date. DD and ID have been reported among others in most of the affected individuals (only the respective features are commented on below): PMID: 28236339 (Musante et al. 2017) : 2 sibs compound heterozygous for NM_201263.2:c.325delA (p.Ser109Alafs*159) and c.37T>G (p.Trp13Gly). DD with ID were features in both. PMID: 28650581 (Theisen et al. 2017) : The authors report on 1 individual with DD, ID and seizures was found to harbor in the compound heterozygous state NM_0158360.3:c.938A>T (p.K313M) and c.298_300delCTT (p.L100del). PMID: 28905505 (Wortmann et al. 2017) : Details on 6 individuals from 5 unrelated families are provided. DD and ID were observed in 5 of these individuals (Fam 2-5). Severe, neonatal presentation was the case for an additional subject. Confirmed occurrence of epilepsy was reported for 3 individuals from 2 families (and suspected in a further one). Using NM_0158360.3 variants were the following : Fam1 : c.91-8725_348+27113del36096 (p.Lys31_Glndel116) in trans with c.1045G>C (p.Val349Leu) Fam2 : c.797del (p.Pro266Argfs*10) in trans with c.938A>T (p.Lys313met) [in 2 individuals] Fam3 : c.231C>G (p.His77Gln) in trans with c.1054G>A (p.Glu352Lys) Fam4 : c.532G>C (p.Val178Leu) in homozygous state Fam5 : c.134G>T (p.Gly45Val) in trans with c.938A>T (p.Lys313Met) PMID: 29783990 (Vantroys et al. 2018) : The authors report on 1 individual with DD, ID and seizures (among other features), compound heterozygous for c.797del (p.Pro266Argfs*10) and c.938A>T (p.Lys313met), similar to subjects from family 2 in PMID: 28905505. PMID: 29120065 (Burke et al. 2018) : One 17-year-old boy with infantile-onset Parkinsonism but not DD/ID is described in this study. This individuals was found to harbor in the following variants in the compound heterozygous state: NM_015836.3: c.37T>G (p.Trp13Gly) and c.683C>G (p.Ser228Trp). Probably 7 missense variants, 3 frameshift ones and an intragenic deletion have been reported in individuals with DD/ID (overview in fig 4. - in PMID: 29783990). - p.Pro266Argfs*10 is located in the last exon of the gene (NM_015836.3). - p.Trp13Gly (c.37T>G using either NM_201263.2 or NM_015836.3 as ref) has been commented to be a functional polymorphism 'uncovered' by the presence of a LoF allele in trans in affected individuals (AF : 0.003265 and 6 homozygotes in gnomAD) - p.Lys313Met is possibly the most frequently reported variant as discussed by Vantroys et al. WARS2 encodes mitochondrial tryptophanyl-tRNA synthetase (a cytoplasmic form is encoded by WARS). As commented in most of the articles, aminoacyl-tRNA synthetases (ARS) are a group of enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in mitochondrial ARSs lead to impaired intramitochondrial translation affecting OXPHOS complexes (with mitochondrial-encoded subunits). Mutations in all 19 mitochondrial ARSs have been linked to disorders affecting different organ systems with variable severity and phenotypic presentation (summarized by Vantroys et al.). Several lines of evidence have been provided to support a role for specific variants (eg. reduced WARS2 amounts upon Western blot, or impaired mitochondrial localization depending on the different variants and their effect) or WARS2 (expression in brain, impaired aminoacylation, abnormalities in OXPHOS enzymes/biosynthesis , etc). Alternative causes (disorders of the differential diagnosis) have been ruled out on most - if not all - occasions. As commented by Wortmann et al. the clinical spectrum appears to be broad as for the age of onset, features and clinical course (as happens to be the case for some other disorders due deficiencies of other ARSs). The same authors state that apart from elevated lactate which is suggestive of mitochondrial dysfunction, no specific metabolite was found to be altered in affected individuals. Phenotypic variability even between individuals with the same genotype has been reported. Eg. severe neonatal presentation with lactic acidosis/hypoglycaemia was the case for 2 sibs in family 2 from Wortmann et al. but the clinical course was different for the subject reported by Vantroys et al. (DD/ID with seizure onset at the age of 6 yrs). As a result, investigations (and selection of gene panel) may not be straightforward. In addition consideration of this gene in the epilepsy panel seems to be relevant given that seizures were noted in at least 5 individuals (from 4 families - 28650581, 28905505, 29783990) and severe adverse effects of valproate administration occurred in the subject reported by Vantroys et al. ----------- The associated phenotype in OMIM is Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (# 617710). WARS2 is not associated with any disorder in G2P. This gene is included in panels for ID offered by some diagnostic laboratories. ----------- As a result, WARS2 can be considered for inclusion in the ID and epilepsy panels as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.690 | NFIB | Ivone Leong Phenotypes for gene: NFIB were changed from Global developmental delay; Intellectual disability; Macrocephaly to Global developmental delay; Intellectual disability; Macrocephaly; Macrocephaly, acquired, with impaired intellectual development, 618286 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.670 | MCM3AP | Ivone Leong Phenotypes for gene: MCM3AP were changed from Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (MIM 618124) to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development, 618124 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.654 | CUX1 |
Konstantinos Varvagiannis gene: CUX1 was added gene: CUX1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: CUX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CUX1 were set to 30014507; 20510857; 25059644 Phenotypes for gene: CUX1 were set to Global developmental delay with or without impaired intellectual development, 618330 Penetrance for gene: CUX1 were set to unknown Review for gene: CUX1 was set to GREEN gene: CUX1 was marked as current diagnostic Added comment: Heterozygous pathogenic variants in CUX1 cause Global developmental delay with or without impaired intellectual development (MIM 618330). Platzer et al. (2018 - PMID: 30014507) report on 9 individuals from 7 families with heterozygous null-allele variants in CUX1. All individuals displayed DD (speech delay 9/9 - motor delay 7/9 - hypotonia 3/7 for whom this information was available). Mild/moderate ID was a feature in 5/8. Catch up was observed in 3/8 individuals who - despite a history of previous significant DD - displayed a normal age-related intelligence. For 1/9 individual (Decipher 338131) information on eventual ID was unavailable. Overall the phenotype was compatible with non-syndromic DD with possible ID. CUX1 encodes Cut homebox-1 transcription factor. 5 LoF variants (Gln21*, Gln800Argfs*19, Gln873*, Ala1067Cysfs*3, Leu1262Argfs*10) and 2 intragenic deletions (deletion of exons 9-24 in one subject and 3-24 in another) are reported. In 6/9 individuals the variant (SNV/CNV) had occurred as a de novo event. Mosaic de novo intragenic deletion was reported for the subject from Decipher. In one family 2 sibs with mild ID had inherited a LoF variant from their affected mother with moderate ID (origin of the variant unknown in her case). Leu1262Argfs*10 lies in the penultimate exon (NM_001202543.1 used as ref.) and is presumed to escape NMD. Expression studies (or functional studies) are not performed for any of the variants. As Gln800Argfs*19, found in one subject with mild ID in the present study, has been reported once in gnomAD, and given the presence of 12 individuals overall with LoF variants in the specific database, plausible explanations are discussed (among others : mild phenotype, incomplete penetrance, somatic mosaicism, exclusion of individuals with severe early-onset disorders in gnomAD, etc). Given the reported variants, the probability of LoF intolerance (pLI:1.00), and the haploinsufficiency score (% HI) of 7.19, haploinsufficiency is thought to be the underlying mechanism. CUX1 however appears to be intolerant also to missense SNVs (z-score : 5.05). Mouse models suggest a role for Cux1 in brain development and signaling. As the authors note, Cux1 (similar to its paralog, Cux2) is selectively expressed in layer II to IV cortical neurons. In Cux1-deficient mice, dendrites display a simpler morphology with decrease in dendritic length and number of branches (PMIDs cited: 20510857, 25059644). (MGI db for Cux1 - http://www.informatics.jax.org/marker/MGI:88568 : "Homozygotes for a targeted null mutation exhibit delayed lung development and neonatal mortality. Survivors show growth retardation and hair defects. Homozygotes for a partially deleted protein have curly hair, and females tend to lose their litters"). Finally, heterozygous mutations in CUX2, encoding cut-like homeobox-2 transcription factor, cause Epileptic encephalopathy, early infantile, 67 (MIM 618141 - in all cases reported to date due to a recurrent missense variant. Gene rated green in the current panel). ------- CUX1 is not associated with any phenotype in G2P. This gene is included in panels for ID offered by diagnostic laboratories (incl. Radboudumc). ------- As a result, CUX1 can be considered for inclusion in the ID panel as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.611 | CYFIP2 |
Konstantinos Varvagiannis gene: CYFIP2 was added gene: CYFIP2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CYFIP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CYFIP2 were set to 29534297; 29667327; 30664714; 25432536; 27524794; 12818175; 20537992 Phenotypes for gene: CYFIP2 were set to Epileptic encephalopathy, early infantile 65, 618008 Penetrance for gene: CYFIP2 were set to unknown Review for gene: CYFIP2 was set to GREEN gene: CYFIP2 was marked as current diagnostic Added comment: Heterozygous pathogenic variants in CYFIP2 cause Epileptic encephalopathy, early infantile, 65 (MIM 618008) -------------- [Apologies for any eventual mistakes esp.as for the functional evidence]: Nakashima et al. (2018 - PMID: 29534297) report on 4 unrelated individuals with early-onset epileptic encephalopathy due to de novo missense CYFIP2 variants. The phenotype consisted of early-onset intractable seizures (diagnosis of West syndrome in 2, Ohtahara syndrome in further individuals) with hypotonia (3/4), DD/ID (4/4) and microcephaly (3/4). All variants affected Arg87 residue (NM_001037333.2:c.259C>T or p.Arg87Cys in 2 individuals, the 2 other subjects harbored Arg87Leu and Arg87Pro respectively). CYFIP2 encodes the cytoplasmic FMRP interacting protein 2. CYFIP2 (similar to CYFIP1) is a component of the WAVE regulatory complex (WRC) which has been shown to play a role in actin remodeling, axon elongation, dendritic morphogenesis and synaptic plasticity (several PMIDs cited). In the inactive state of the WRC complex, CYFIP2 binds to the VCA domain of WAVE. GTP-bound Rac1 (GTPase) leads to release of the VCA domain from CYFIP2 which allows binding of this domain to the Arp2/3 complex (active WRC state) and in turn stimulates actin polymerization and lamellipodia formation. Using lymphoblastoid cell lines from affected individuals and healthy controls and CYFIP2 expression was evaluated by Western Blot and was found to be similar between the 2 groups. Additional studies suggested weaker binding of the WAVE1 VCA domain to mutant CYFIP2 compared to WT CYFIP2 (upon transfection of HEK293T cells). This could possibly favor activation of WRC (/the WAVE signalling pathway). As a result a gain-of-function effect on the WAVE signalling pathway is suggested as a possible mechanism. Using B16F1 mouse melanoma cells lamellipodia formation (process in which CYFIP2 has previously been implicated) was not shown to be impaired in the case of mutant CYFIP2. However aberrant accumulation of F-actin (and co-localization with mutant CYFIP2) was observed in the present study. Only large 5q deletions spanning CYFIP2 (and several other genes) have been described to date. Cyfip2 heterozygous knockout in mice results in abnormal behavior and memory loss. WAVE activity was enhanced (despite reduced WAVE protein production). Homozygous Cyfip2 loss is lethal (PMIDs cited by the authors: 25432536, 27524794). Impaired axonal growth, guidance and branching is noted in Drosophila mutants (CYFIP1/2 ortholog) (PMID cited: 12818175). The authors comment that Cyfip2 (nev) mutant zebrafish show a similar phenotype to mutant flies (PMID cited: 20537992). -------------- Peng et al. (2018 - PMID: 29667327) in a study of 56 Chinese families with West Syndrome (epileptic/infantile spasms, hypsarrhytmia and ID) identified 1 individual with the Arg87Cys CYFIP2 variant as a de novo occurrence. -------------- Zweier et al. (2019 - DDD study among the co-authors - PMID: 30664714) report on 12 unrelated subjects with heterozygous pathogenic de novo CYFIP2 variants. The common phenotype consisted of tone abnormalities (12/12), DD/ID (12/12) and seizures (12/12 though a single individual had experienced a single episode of febrile seizure). Absolute or relative microcephaly and/or additional features were also noted in several individuals. 7 missense variants (4 occurrences of the Arg87Cys variant) as well as splice variant (shown to lead to exon skipping) are reported, as de novo events in these individuals. The splice variant was expected to escape NMD producing a truncating protein. Although the variants are distantly located in the primary structure, spatial clustering (in the tertiary structure) is suggested by in silico modelling (all in proximity at the CYFIP2-WAVE1 interface). CYFIP2 appears to be intolerant to both missense and LoF variants (Z-score of 6.15 and pLI of 1 respectively in ExAC). The authors comment that haploinsufficiency as a mechanism is rather unlikely given the absence of small CNVs or variants predicted to lead to NMD. Again, a gain-of-function effect of these variants on WAVE activation (partial-loss-of function in terms of WRC stabilization and/or conformation of the VCA region in the inactive state) is proposed. -------------- CYFIP2 is not associated with any phenotype in G2P. The gene is included in gene panels for intellectual disability offered by some diagnostic laboratories (eg. participants in these studies). -------------- As a result this gene could be considered for inclusion in this panel as green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.597 | PLEKHG2 |
Konstantinos Varvagiannis gene: PLEKHG2 was added gene: PLEKHG2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PLEKHG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PLEKHG2 were set to 26539891; 26573021; 24001768 Phenotypes for gene: PLEKHG2 were set to Leukodystrophy and acquired microcephaly with or without dystonia, 616763 Penetrance for gene: PLEKHG2 were set to unknown Review for gene: PLEKHG2 was set to AMBER gene: PLEKHG2 was marked as current diagnostic Added comment: Karaca et al. (2015 - PMID: 26539891) in a study of 128 - mostly consanguineous - families with neurogenetic disorders and brain malformations, identified an individual homozygous for a PLEKHG2 missense variant (NM_022835.2:c.1708G>A or p.Gly570Arg). This individual (BAB4830) had a similarly affected sib. Features included hypotonia, intellectual disability, microcephaly, cerebellar atrophy and nystagmus (description provided in supplement - Table S1). This variant has been submitted in ClinVar as likely pathogenic by the corresponding laboratory (SCV000537940.1). ------- Edvardson et al. (2016 - PMID: 26573021) reported on 5 individuals from 2 unrelated consanguineous Palestinian families, harboring a missense variant in the homozygous state (NM_022835.2:c.610C>T or p.Arg204Trp - 1/5 was unavailable for testing). Unaffected relatives here either heterozygous for this variant or homozygous for the reference allele. Common features included hypotonia (5/5), DD/ID (5/5), postnatal microcephaly (5/5), dystonia (3/5), nystagmus (2/5) or seizures (1/5) [many of these similar to those reported by Karaca et al]. Brain MRI images were consistent with leukodystrophy and prolonged relaxation of dorsal tegmental tracts (similar findings were not commented by Karaca et al). PLEKHG2 encodes a Rho guanine exchange factor (RhoGEF). RhoGEFs activate RhoGTPases through release of GDP and binding of GTP. Mutations in other RhoGEFs have been associated with neurodevelopmental disorders. PLEKHG2 activity was shown to be significantly decreased in HEK293A cells transfected with R204W-PLEKHG2 when compared to tranfection with wt. Western blotting suggested that this was not the result of defective expression. Using lymphoblastoid cell lines from peripheral B lymphocytes from individuals homozygous for R204W and controls, similar levels of expression were shown between the 2 groups. As the authors note, PLEKHG2 is required for Rac- and Cdc42-stimulated actin polymerization in leukocytes (PMID cited: 24001768). SDF1a-stimulated actin polymerization was studied in patient cells and was shown to be significantly impaired. In line with this actin polymerization was also impaired upon siRNA-mediated downregulation of PLEKHG2 expression in control cells. ------- A subsequent submission of the Gly570Arg variant in ClinVar (2017 - SCV000609979.1 - same variant as the one reported by Karaca et al) reports this as a VUS. ------- PLEKHG2 is associated with Leukodystrophy and acquired microcephaly with or without dystonia (616763) in OMIM. This gene is not associated with any phenotype in G2P. PLEKHG2 is included in gene panels for ID offered by some diagnostic laboratories. ------- As a result, this gene could be considered for inclusion in this panel probably as amber (or green if the current evidence is considered to be sufficient). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.597 | SOX4 |
Konstantinos Varvagiannis gene: SOX4 was added gene: SOX4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SOX4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: SOX4 were set to Global developmental delay; Intellectual disability; Growth delay; Clinodactyly of the 5th finger; Abnormality of head or neck Penetrance for gene: SOX4 were set to unknown Review for gene: SOX4 was set to GREEN Added comment: Zawerton et al. (DDD study among the co-authors - doi.org/10.1016/j.ajhg.2018.12.014 - PMID:NA) report on 4 unrelated individuals with de novo SOX4 pathogenic variants. The common phenotype consisted of DD/ID (4/4 - very mild to severe), overlapping facial features as well as digital anomalies (5th finger clinodactyly in 4/4). SOX4 is a member of the SOX family of transcription factors, all presenting at least 50% identity with SRY (the first identified member of this family) in the HMG (DNA-binding) domain. Most SOX genes have important roles in cell fate / differentiation. Mutations in other genes of this family (eg. SRY, SOX9, SOX10, SOX5) are associated with severe human syndromes. SOX4 is highly expressed in human brain during gestation - particularly in areas of active neurogenesis - with progressive decrease thereafter until the 3rd - 4th decade of life. Knockdown of the SOX4 ortholog in Xenopus laevis embryos resulted in smaller head size, microphthalmia, shorter body length and underdevelopment of fore- and mid-brain. (Growth deficiency was a common feature in affected individuals, and microcephaly in 2/4). Sox4-null mice die in utero due to heart septation defects, while such abnormalities were not reported in heterozygous mice. One affected subject had a VSD. Sox4 inactivation in mice results in impaired skeletal growth (similarly to the patients). All 4 different missense variants clustered in the HMG domain (aa 58-133) which appears relatively (more) depleted in missense variants (only 12 missense HMG-domain variants in gnomAD). [Overall the Z-score for missense variants is 3.72. pLI = 0.38. %HI in DECIPHER : 24.67%]. The 4 missense variants presented impaired DNA binding and transcription activation in COS-1 transfected cells which appeared to distinguish them from the 12 gnomAD ones. Synthesis, stability and nuclear translocation appeared to be similar to wt. Other parameters eg. residue conservation in the SOX family, presence of "equivalent" known disease causing mutations in other SOX genes or in silico analyses suggesting structural consequences were supportive of a deleterious effect for the 4 variants (but also for some of the 12 gnomAD ones). SOX4 and SOX11 have almost identical DNA-binding domains, while the mechanism of mutations reported and the phenotypes appear to be relatively similar, as commented by the authors. -------------- SOX4 is not associated with any phenotype in G2P, nor in OMIM. This gene is not - at least commonly - included in gene panels for ID offered by diagnostic laboratories. -------------- As a result SOX4 can be considered for inclusion in the ID panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.595 | NUS1 |
Konstantinos Varvagiannis gene: NUS1 was added gene: NUS1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: NUS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779 Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function Penetrance for gene: NUS1 were set to unknown Review for gene: NUS1 was set to AMBER gene: NUS1 was marked as current diagnostic Added comment: Mutations in NUS1 have been implicated in recessive as well as dominant forms of ID (1 and 3 unrelated individuals respectively). The latter individuals presented with a developmental and epileptic encephalopathy with ID. At least 2 of these individuals had tremor and other movement disorders. A recent study proposes that NUS1 variants contribute to Parkinson's disease (1 individual with de novo variant affecting the canonical splice site, 26 additional individuals with missense variants - for which segregation studies where not however performed). ID is not commented on for these individuals. NUS1 is included in the DD panel of G2P, associated with "Epilepsy and intellectual disability". (Monoallelic LoF variants / Disease confidence : probable). This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). Associated phenotypes in OMIM and others discussed in the literature are summarized below (to my understanding). As a result, NUS1 can be considered for inclusion in the ID panel probably as amber. -------- Recessive - [MIM #617082 - ?Congenital disorder of glycosylation, type 1aa] : Park et al. (2014 - PMID: 25066056) report on an individual homozygous for a NUS1 missense variant (R290H) and suggest that biallelic variants cause a congenital disorder of glycosylation. The authors based in studies in yeast, mice and man provide evidence that NUS1 encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), important for its activation. cis-PTase catalyzes one of the reactions for dolichol biosynthesis. Dolichol, in turn, is a carrier of glycans for N-linked glycosylation, O-mannosylation and GPI anchor biosynthesis. Genetic defects in the dolichol biosynthetic pathway have been linked to other forms of CDG and/or other recessive or dominant neurodevelopmental disorders (eg. SRD5A3- and DHDDS-related disorders). Similarities are provided at the cellular level between different organisms. Heterozygous knockout mice appear normal. Homozygosity is associated with embryonic lethality before E6.5. Conditional knockout in mouse embryonic fibroblasts led to accumulation of free cholesterol, decreased cis-PTase activity, and mannose incorporation in protein (the first & third rescued by transduction with lentiviral human NgBR). In patient fibroblasts protein levels appeared similar to controls. Interaction with Nogo-B (and hCIT - the product of DHDDS) was not affected. As in mice, accumulation of free cholesterol was observed in cells, with decreased cis-PTase activity and mannose incorporation. LAMP-1 and ICAM-1 were hypoglycosylated in patient fibroblasts. Altered dolichol profiles in serum and urine were observed in carriers of the NUS1 variant, similarly to what described in individuals with DHDDS LoF variants. ---------- Dominant - [MIM #617831 - Mental retardation, autosomal dominant 55, with seizures]. Hamdan et al. (2017 - PMID: 29100083) report on 3 unrelated individuals with developmental and epileptic encephalopathy (onset: 10m - 2.5y) and ID. Two individuals harbored de novo LoF variants while a third subject had a deletion of exon 2. Movement disorders were noted in all 3 and included tremor (2 subjects) or ataxia (1 additional subject). The authors cite a previous study on 6q22.1 deletions the critical region of which encompassed only NUS1 and the promoter of SLC35F1 (Szafranski et al. - PMID: 24824130). Haploinsufficiency is discussed as a possible mechanism (pLI of 0.87). A more severe phenotype due to dramatic reduction of NUS1 activity is proposed for the previously reported patient with CDG. ---------- Other: Guo et al. (2018 - PMID: 30348779) suggest that NUS1 pathogenic variants contribute to Parkinson's disease. By performing WES in 39 individuals with early onset Parkinson's disease and their unaffected patients (and sibs) the authors identified 1 individual with de novo insertion affecting a NUS1 canonical splice site. RT-PCR demonstrated increased mRNA levels compared with controls. Skipping of 91 bp of exon 3 was demonstrated. Study in 2 large sporadic PD-patient (N=1852+3237)/control cohorts (N=1565+2858) suggested association between NUS1 non-synonymous variants and PD (P=1.01e-5, OR:11.3). Other genetic causes of PD were excluded in 26 additional individuals with NUS1 missense variants. Phenotypes of all 27 individuals are provided in Dataset_S04. NUS1 has been found to be differentially expressed in PD mouse models. RNAi-mediated knockdown of Tango14 (the Drosophila NUS1) resulted in impaired climbing activity, reduction in brain dopamine levels and abnormal apoptotic signals in brain. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.595 | STAG2 |
Konstantinos Varvagiannis gene: STAG2 was added gene: STAG2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: STAG2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: STAG2 were set to 29263825; 28296084; 30158690; 30447054; 19449417; 26443594; 25677961; 23637084; 25450604 Phenotypes for gene: STAG2 were set to Global developmental delay; Intellectual disability; Abnormality of head or neck; Microcephaly; Growth delay; Hearing impairment; Abnormal heart morphology Penetrance for gene: STAG2 were set to unknown Review for gene: STAG2 was set to GREEN gene: STAG2 was marked as current diagnostic Added comment: Several affected individuals (from at least 8 unrelated) families have been reported in the literature. The phenotype consists - among others - of DD/ID. STAG2 is located on long arm of chromosome X (Xq25). Based on these reports, both males and females can be affected. Soardi et al. (2017 - PMID: 29263825) report an affected male belonging to a large pedigree with 4 other similarly affected males. The disorder in this pedigree followed a typical X-linked inheritance pattern. All affected males were hemizygous for a missense variant (NM_001042749.1:c.980G>A or p.Ser327Asn). Common phenotype consisted of moderate ID, short stature, sensory hearing loss and some similar facial features. Unaffected males did not harbor the variant. Heterozygous females were not affected. Co-segragation of the variant with the affected status under an X-linked model, appeared unlikely to have occurred by chance (probability of 1/131,072 - logarithm of odds score of 5.12). Mullegama et al. (2017 - PMID: 28296084) report on an 8-year-old girl harboring a de novo nonsense variant in STAG2 (NM_001042749.1:c.205C>T or p.Arg69Ter). This individual presented - among others with - DD, microcephaly, growth delay, digit anomalies, particular facial features, and anomalies of other systems (eg. hearing loss, cardiac defect, etc). The authors summarize the features of 2 subjects from the DDD study as available in DECIPHER, without additional details. [Variants of these individuals NM_001042749.1:c.1913_1922del10 or p.(A638Vfs*10) / NM_001042749.1:c.1811G>A p.(R604Q)]. Yuan et al. (2018 - PMID: 30158690) report on 4 females with de novo LoF STAG2 variants as well as 1 male subject with a de novo missense one. DD (5/5) and ID (4/4) were features in all individuals for whom this information was available. One additional female had an intragenic STAG2 deletion, although this subject was not reported to have DD or ID (table S6 : microcephaly, seizures and facial phenotype). It is not known whether the deletion was inherited or had occurred as a de novo event. All variants from this study have been submitted in ClinVar (phenotype : STAG2-related disorder). Mullegama et al. (2018 - PMID: 30447054) report on a 4-year-old male with DD, microcephaly, growth delay, digit anomalies due to a de novo missense STAG2 variant (c.3027A>T or p.Lys1009Asn). As discussed by the authors at the time of the study 33 males with Xq25 duplications and ID had been reported (PMIDs cited: 19449417, 26443594, 25677961, 23637084, 25450604). Discussed in these articles : STAG2 (or STAG1) is one of the 4 core proteins of the cohesin complex, the other 3 being SMC1A, SMC3 and RAD21. Mutations in genes encoding these proteins or their interactors (eg. NIBPL, HDAC8, ESCO2, etc) have been associated cohesinopathies, a group of multisystem developmental disorders (eg. Cornelia de Lange syndrome, Roberts/SC phocomelia, etc). It has been commented that the phenotype of STAG2-related disorder presents overlap with other cohesinopathies (eg. DD, microcephaly and growth retardation, craniofacial features, anomalies of the digits, etc). Decreased proportion of nuclei with premature sister chromatid separation compared to controls was found on one occasion (suggestive of tighter sister chromatid cohesion) [Mullegama-A]. Sister chromatid cohesion was not affected in another report [Soardi et al.]. Western blot demonstrated significant reduction of STAG2 levels for a nonsense variant [Mullegama-A]. Levels were not perturbed for a missense variant [Soardi et al.]. Upon immunofluorescence STAG2 presented normal (nuclear) localization for a missense variant for which this was studied [Soardi et al.]. Perturbation of the cell cycle profile (higher percentage of G2/M cells) was demonstrated for patient fibroblasts compared to controls on one occasion where this was studied. [Soardi et al.]. Microarray expression studies in patient fibroblasts demonstrated altered transcription (upregulation) of genes implicated in cell division, mitosis and DNA replication upon comparison with normal fibroblasts [Soardi et al.]. The effect of a missense variant on STAG2 binding to other cohesin subunits (SCC1, SMC1 and SMC3) and regulators was studied. Binding was found to be reduced in vivo (in HeLa cells) for SCC1 (its direct binding partner) as well as SMC1, SMC3 (possibly indirectly). Reduced STAG2 binding to cohesin regulators was also shown in vivo. However, in vitro studies were not suggestive of impaired binding of STAG2 to SCC1 (a finding difficult to explain) [Soardi et al.]. STAG2 appears to be intolerant to LoF variants (pLI of 1 in ExAC). Z-Score for missense variants is 5.11. Mullegama et al. (B) comment that Xq25 duplications in males may be associated with milder phenotypes compared to intragenic variants. They further hypothesize that males are able to survive less damaging variants while females are able to survive more deleterious (eg. LoF) ones though with more severe phenotypes (similarity to the MECP2 model is discussed). ---------- STAG2 is not associated with any phenotype in OMIM. In G2P this gene is associated with STAG2-related developmental delay with microcephaly and congenital anomalies (disease confidence : confirmed / Both DD and ID among the phenotypes assigned to this entry). ---------- STAG2 is included in gene panels for ID offered by some diagnostic laboratories. ---------- As a result, this gene can be considered for inclusion in the ID panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.595 | ZMIZ1 |
Konstantinos Varvagiannis gene: ZMIZ1 was added gene: ZMIZ1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZMIZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZMIZ1 were set to 29754769; 18053775; 17967885; 26163108; 27479843 Phenotypes for gene: ZMIZ1 were set to Global developmental delay; Intellectual disability; Feeding difficulties; Growth abnormality; Microcephaly; Abnormality of the skeletal system; Abnormality of the urinary system; Abnormality of the cardiovascular system; Abnormality of head or neck Penetrance for gene: ZMIZ1 were set to unknown Review for gene: ZMIZ1 was set to GREEN gene: ZMIZ1 was marked as current diagnostic Added comment: Carapito et al. (doi.org/10.1016/j.ajhg.2018.12.007 - PMID to add) report on 19 individuals with variants affecting ZMIZ1 (alternative symbols RAI17/KIAA1224/ZIMP10). Features included DD/ID (19/19), feeding difficulties, growth failure, microcephaly and variable congenital malformations. Seizures were noted in 3 unrelated individuals (with different variants). Variants included 6 missense SNVs, 5 frameshift variants, 1 splice site variant, 1 synonymous variant with probable impact on splicing (not studied) and 2 translocations. In all individuals for whom parental studies were possible (n=16), the variants had occurred as de novo events while for 3 sibs harboring a frameshift variant parental samples were unavailable. These subjects however harbored the same variant as a DDD study participant included in the current report. One translocation disrupted only ZMIZ1 while a second [t(X;10)] did not disrupt the coding sequence of any gene but only a distal enhancer 276 kb upstream of ZMIZ1. A previous study had found recurrent SNVs of the same region in ASD subjects and suggested possible interaction with the ZMIZ1 promoter (Liu et al. - PMID: 29754769). The deleterious effect of both translocations was confirmed by quantitative RT-PCR. For 4 missense SNVs as well as a splice variant mRNA levels were similar to controls. The splice site (-2) variant was shown to produce 2 new splicing isoforms from utilization of alternative splice site acceptors. ZMIZ1 belongs to the PIAS-like family of transcriptional coregulators. Five missense variants were located in an alanine rich domain (aa 280-305). Seven other variants were predicted to shorten or remove the C-terminal transactivation domain. This gene enhances - among others - the transcriptional activity of androgen receptor (AR). In vitro studies using HEK293T cell lines supported impaired coactivation of the AR for 3 variants studied. In utero electroporation of pathogenic variants in mouse embryos (E14.5) led to impaired neuronal positioning of the electroporated neurons and disruption of the morphology/polarization. As the authors note previous studies have shown expression of Zimp10 in the developing mouse brain, craniofacial tissue as well as the interdigital region of limbs (PMIDs cited : 18053775 and 17967885) in line with ID, facial phenotype and syndactyly observed in some patients. Finally the authors cite a previous report on an individual with ID due to a translocation [t(10;19)] disrupting both ZMIZ1 and PRR12 (Córdova-Fletes al. - PMID: 26163108). Although disruption of ZMIZ1 is discussed as a cause, PRR12 has recently been proposed as (also) an ID gene (Leduc et al. - PMID: 29556724). [For details see PRR12 in the current panel]. ------------ One of the variants found in 2 unrelated individuals in the aforementioned study [NM_020338.3:c.899C>T or p.(T300M)] has been reported in a further individual investigated for ID in the context of a bigger cohort (Lelieveld et al. - PMID: 27479843). [ Details in the denovo-db : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=ZMIZ1 ] ------------ ZMIZ1 is not associated with any phenotype in OMIM, nor in G2P. This gene has been included in gene panels for intellectual disability offered by some diagnostic laboratories. ------------ As a result, ZMIZ1 can be considered for inclusion in the ID panel as green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.588 | MAPK8IP3 |
Konstantinos Varvagiannis gene: MAPK8IP3 was added gene: MAPK8IP3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: MAPK8IP3 were set to 25363768; 28213671; 28135719 Penetrance for gene: MAPK8IP3 were set to unknown Review for gene: MAPK8IP3 was set to GREEN Added comment: Platzer et al. (doi.org/10.1016/j.ajhg.2018.12.008) report on 13 unrelated individuals with de novo pathogenic variants in MAPK8IP3. The phenotype consisted - among others - of DD with ID (13/13) as well as variable brain anomalies (incl. cerebral or cerebellar atrophy, corpus callosum anomalies, perisylvian polymicrogyria, etc). Microcephaly, seizures, ataxia, ASD were features seen in fewer individuals. The variants reported included 2 nonsense, 1 frameshift as well as 6 missense mutations (3 missense variants were found - each - in 2 or more individuals). All three LoF variants were located in the first exon. (mRNA levels were not studied for these variants although NMD is presumed). The brain anomalies were more consistent for missense variants. MAPK8IP3 appears intolerant to LoF variants (pLI of 1) with constraint also for missense variants (Z-score of 4.06). In silico structural modeling was possible for 4 missense variants based on available crystal structures and different mechanisms were presumed (disruption of contacts between Leu444 of adjacent subunits, altered interaction between proximal residues at positions 461 and 466, or disruption of protein protein interactions). The C.elegans MAPK8IP3 ortholog is encoded by the unc-16 gene. Impaired clearance and accumulation of organelles (incl. lysosomes) in axons is observed in unc-16 mutants (recessive phenotype). For 6 variants, also conserved in C.elegans, mutants were engineered using CRISPR genome editing. The observed mutant phenotypes (increased axonal lysosomal density compared to controls for 2 variants, sluggish locomotion with lower swimming cycle rate for 1 nonsense and 4 missense variants) were rescued upon CRISPR reverse engineering of each mutant allele back to its wild-type sequence. The authors cite 3 previous studies, in which individuals investigated for neurodevelopmental disorders where found to harbor de novo MAPK8IP3 variants, namely: - PMID 25363768 (Iossifov et al.) : p.Tyr94Cys [ASD without ID] - PMID 28213671 (Berger et al.) : p.Glu461Gly [Smith-Magenis-like phenotype) - PMID 28135719 (DDD study) p.Arg1146Cys [This variant was found in 3 individuals in the study by Platzer et al.] ------------ A few additional individuals with neurodevelopmental disorders appear in the denovo-db after filtering for coding variants: http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=MAPK8IP3 ------------ NM_015133.4:c.111C>G (p.Tyr37Ter) has been submitted in ClinVar by the Undiagnosed Diseases Network (NIH) as likely pathogenic, associated with MAPK8IP3-related disorder (hypotonia, DD, EEG anomalies among the phenotypes). It is not clear whether this subject corresponds to individual #3 reported by the previous study (possibly not the case). ------------ MAPK8IP3 is not associated with any phenotype in OMIM, nor in G2P. This gene is not commonly included in gene panels for ID. ------------ As a result, MAPK8IP3 can be considered for inclusion in this panel as green (rather than amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.588 | CTNNA2 |
Konstantinos Varvagiannis gene: CTNNA2 was added gene: CTNNA2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CTNNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTNNA2 were set to 30013181 Phenotypes for gene: CTNNA2 were set to Cortical dysplasia, complex, with other brain malformations 9 (MIM 618174) Penetrance for gene: CTNNA2 were set to Complete Review for gene: CTNNA2 was set to AMBER Added comment: Biallelic loss-of-function mutations in CTNNA2 cause cortical dysplasia, complex, with other brain malformations 9 (MIM 618174). ------- Schaffer et al. (PMID: 30013181) report on 7 individuals from 3 unrelated consanguineous families. All individuals presented with profoundly impaired motor and cognitive development (severe ID in 6/7 for whom this information was available, all 6 from 2 families - a further individual from the 3rd family was non-ambulatory with absent speech at the age of 28 months), with acquired microcephaly and intractable seizures (7/7 - onset: 6m-3y - atonic/myoclonic/infantile spasms). Pachygyria without posterior-anterior gradient or focal dysplasias was common to all. CTNNA2 encodes αN-catenin. It is expressed in human fetal brain, mainly in regions expressing migration markers DCX and TUJ1. Reduced migration was shown for iPSC-derived neural progenitor cells from an affected individual, compared to controls. The protein contains a putative actin-binding domain (ABD) at its C terminus. Several lines of evidence are provided that this domain is critical for the process of neuronal migration. ------- CTNNA2 is included in the DD panel of G2P associated with disordered cortical neuronal migration (Disease confidence: probable / ID and seizures among the phenotypes assigned to this entry). This gene is not commonly included in gene panels for intellectual disability. ------- As a result CTNNA2 could be considered for inclusion in this panel as amber or possibly green. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.574 | MCM3AP |
Konstantinos Varvagiannis gene: MCM3AP was added gene: MCM3AP was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MCM3AP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCM3AP were set to 24123876; 28633435; 28969388; 29982295 Phenotypes for gene: MCM3AP were set to Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (MIM 618124) Penetrance for gene: MCM3AP were set to Complete Review for gene: MCM3AP was set to AMBER gene: MCM3AP was marked as current diagnostic Added comment: Biallelic mutations in MCM3AP cause Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (MIM 618124). All relevant publications [PMIDs: 24123876, 28633435 (first detailed description of a series of patients with functional studies), 28969388, 29982295) are summarized in OMIM. Overall more than 18 patients from 10 families and at least 8 pathogenic variants have been reported. Apart from abnormal motor development which may be associated with the sensorimotor neuropathy, intellectual disability was a feature in several individuals (although not a universal one). Some patients were initially evaluated for their ID while investigations for the neuropathy may be conducted late (as evident in PMID: 28633435). MCM3AP is included in gene panels for intellectual disability offered by diagnostic laboratories. As a result, this gene can be considered for inclusion in the ID panel as amber or green (depending on its relevance to the specific panel). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.558 | FBXL3 |
Konstantinos Varvagiannis gene: FBXL3 was added gene: FBXL3 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: FBXL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FBXL3 were set to 30481285 Phenotypes for gene: FBXL3 were set to Intellectual disability; Short stature Penetrance for gene: FBXL3 were set to Complete Review for gene: FBXL3 was set to GREEN Added comment: Ansar et al. (PMID: 30481285) report on 8 individuals from 3 consanguineous families, all homozygous for FBXL3 variants. The phenotype consisted of mild to severe intellectual disability (8/8), short stature (8/8) with a few common facial features. In the first family - from Pakistan - all affected individuals were homozygous for a frameshift variant. The 2 sibs from the second family (from Lebanon) were homozygous for a nonsense variant. A further patient, born to distantly related parents from Italy, was found to harbor a missense variant [NM_012158.2:c.1072T>C or p.(Cys358Arg)] in the homozygous state. FBXL3 is part of an ubiquitin ligase complex that binds the central clock protein cryptochromes (CRY1/2) mediating their degradation. Cys358Arg concerns the same codon as a similar - previously studied - variant (Cys358Ser) reported to affect the mouse circadian rhythm. Disturbance of circadian rhythm was observed in the patient with the Cys358Arg variant. As previously demonstrated for mutations of the same codon and in line with a pathogenic role for this variant, in silico studies predict impaired interaction of FBXL3 with CRY2. It is proposed that the nonsense and frameshift variants lead to a similar effect due to severe truncation of the protein (upstream of leucine-rich domains important for this interaction). The authors note that other F-box proteins are implicated in intellectual disability (as in the case of FBXO11 and FBXL4, both rated green in this panel). As a result, FBXL3 can be considered for inclusion in this panel as green (or amber). Sources: Literature, Expert Review |
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| Intellectual disability - microarray and sequencing v2.530 | CHD3 |
Konstantinos Varvagiannis gene: CHD3 was added gene: CHD3 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: CHD3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CHD3 were set to 30397230 Phenotypes for gene: CHD3 were set to Global developmental delay; Intellectual disability; Macrocephaly Penetrance for gene: CHD3 were set to unknown Review for gene: CHD3 was set to GREEN Added comment: PMID 30397230 is a collaborative study reporting on the phenotype of 35 individuals including 4 subjects from the DDD study, (most) with de novo mutations in CHD3. Common features include developmental delay, variable degrees of intellectual disability, impaired speech and language (all 3 were universal features) as well as macrocephaly (in approximately 60%) or vision problems. Widely spaced eyes and high/broad/prominent forehead were among the most constant facial features (noted in around 80% each). The majority of the variants reported are missense and cluster within the helicase domain although exceptions of missense variants in other domains or loss-of-function variants are provided. A few variants were recurrent and/or concerned the same residue. Two pairs of affected siblings are reported, in one case this was explained by maternal mosaicism for the mutation. Perturbed ATPase and/or chromatin remodeling activity relative to wild-type were demonstrated although both gain and loss of these activities were noted depending on the variant tested. CHD3 is intolerant to both loss-of-function and missense variants (pLI of 1.0 and Z-score of +7.15). As a result this gene can be considered for inclusion in the ID panel as green. Sources: Expert Review, Literature |
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| Intellectual disability - microarray and sequencing v2.530 | RHOBTB2 |
Konstantinos Varvagiannis gene: RHOBTB2 was added gene: RHOBTB2 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: RHOBTB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RHOBTB2 were set to 29276004; 29768694; 26740508 Phenotypes for gene: RHOBTB2 were set to Global developmental delay; Intellectual disability; Seizures; Postnatal microcephaly Penetrance for gene: RHOBTB2 were set to unknown Mode of pathogenicity for gene: RHOBTB2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: RHOBTB2 was set to GREEN gene: RHOBTB2 was marked as current diagnostic Added comment: PMID: 29276004 reports on 10 unrelated patients with de novo pathogenic missense variants in RHOBTB2. The phenotype in all individuals was compatible with a developmental and epileptic encephalopathy including early-onset seizures, severe intellectual disability, postnatal onset microcephaly (6/10) and movement disorders (8/10). The variants occured as de novo events and clustered within the BTB-domain encoding region (within and between the 2 BTB domains). Three missense variants were recurrent and/or concerned the same residue (p.Arg483His in 4 individuals, Arg511Gln was reported in 2, and Arg511Trp was was found in another 2 individuals). Functional studies in HEK293 cells suggested increased abundance of the mutant protein secondary to decreased proteasome degradation. Using Drosophila as a model organism, altered expression of RhoBTB (the single ortholog of the 3 vertebrate paralogs, closest to RHOBTB2) was shown to result in neurological phenotypes. RhoBTB overexpression in particular was associated with increased bang sensitivity (which was not the case or milder in the case if knockdown of this gene) and impaired performance upon the negative geotaxis assay, similar to the human neurological phenotypes. Altered RhoBTB dosage was shown to be associated with impaired dendrite development. As commented by the authors, these results as well as the clustering of missense variants and the pLI score of 0.51 reported for RHOBTB2 are consistent with altered protein function (due to the missense variants) rather than haploinsufficiency or loss-of-function. PMID: 29768694 describes 3 additional individuals, all found to harbor de novo missense variants again within the BTB-domain encoding region. Two of the variants had been reported in the previous study (Arg511Gln and Arg483His) while the third was a private one (Arg507Cys). The phenotype was similar to the previous descriptions. Functional studies were suggestive of impaired degradation of the mutant protein by the CUL3 complex although this was not secondary to decreased binding with CUL3. PMID: 26740508 (cited by the two aforementioned publications) reports briefly on an individual with de novo missense variant in the same region of RHOBTB2 (Asn510Asp) and Rett-like phenotype. RHOBTB2 is included in gene panels for intellectual disability offered by different diagnostic laboratories. As a result the gene can be considered for inclusion in the intellectual disability and epilepsy panels as green. Sources: Expert Review, Literature |
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| Intellectual disability - microarray and sequencing | AIRE | BRIDGE consortium edited their review of AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | AIRE | BRIDGE consortium edited their review of AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | AIRE | Louise Daugherty classified AIRE as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | AIRE | Louise Daugherty commented on AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | AIRE | BRIDGE consortium reviewed AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||