| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intellectual disability - microarray and sequencing v5.502 | CLEC16A |
Sarah Leigh edited their review of gene: CLEC16A: Added comment: Heterozygous CLEC16A variants have been identified as a genetic risk factor for several autoimmune disorders and for Parkinson disease (PMID: 37175930). PMID: 36538041 reports the neurological effect of homozygous terminating CLEC16A variants in two families. In family 1, the first child died at 5 months, he had progressive microcephaly, failure to thrive and cranial CT showed brain atrophy, dilatation of both central and peripheral liquor spaces, hypoplasia of the corpus callosum (no genetic testing was done), the third pregnancy was terminated (17 weeks of gestation) after prenatal ultrasound showed ventriculomegaly, agenesis of corpus callosum (no genetic testing was done), the fourth pregnancy was also terminated (22 weeks of gestation) as the prenatal ultrasound showed agenesis of corpus callosum. This fetus was homozygous for NM_001243403.1(CLEC16A):c.2062 + 5G > A, RT-PRC showed that this variant resulted in the deletion of exon 19 and a frame shift. Both parents and an unaffected sibling were heterozygous for this variant. In family 2, a single affected child was homozygous for NM_001243403.1(CLEC16A):c.-4_12del, p.Met1fs*. This child had progressive microcephaly, failure to thrive, severe global developmental delay, global brain atrophy and died at 6 years. There is no genetic data from the parents or unaffected siblings in Family 2. PMID: 37175930, also presents zebrafish experiments, where mutagenesis of clec16a by CRISPR–Cas9 resulted in accumulated acidic/phagolysosome compartments, in neurons and microglia, and dysregulated mitophagy. This was rescued by wild type CLEC16A, but not by the C-terminal truncated variant. The authors conclude that dysregulation of CLEC16A-mediated endosomal sorting is associated with neurodegeneration.; Changed rating: GREEN; Changed publications to: 36538041; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.495 | SNF8 |
Achchuthan Shanmugasundram changed review comment from: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism. Sources: Literature; to: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism. This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.495 | SNF8 |
Achchuthan Shanmugasundram gene: SNF8 was added gene: SNF8 was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: SNF8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SNF8 were set to 38423010 Phenotypes for gene: SNF8 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 Review for gene: SNF8 was set to GREEN Added comment: PMID:38423010 reported nine individuals from six families presenting with a spectrum of neurodevelopmental/ neurodegenerative features caused by biallelic variants in SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy with leukoencephalopathy and early death in three of those cases. Two individuals died too young to develop epilepsy. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile) as compound heterozygous. Functional studies using fibroblasts derived from patients and zebrafish model showed loss of function as the disease mechanism. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.487 | ZFX |
Sarah Leigh changed review comment from: A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508). PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model.; to: To date, germline variants in ZFX have not been associated with a phenotype in OMIM or Gen2Phen. A single ZFX variant has been associated with a neurodevelopmental disorder, that has a Rett syndrome-like phenotype disorder, in a 14 year old male. The ZFX variant was allelic with another X-linked variant in SHROOM4. These variants were inherited from the mother, who had random X inactivation pattern (PMID: 26740508). PMID: 38325380 reports 11 ZFX variants in 18 subjects from 16 unrelated families (14 males and 4 females) with an X-linked neurodevelopmental disorder with recurrent facial gestalt. Seven variants were truncating and the remaining were missense variants within the Zinc finger array. In the pedigree of family 6 (figure 3, PMID: 38325380), it was apparent that there were female carriers of the ZFX variant (GRCh38 chrX: 24229396A>G, c.2438A>G, p.Tyr774Cys) with hyperparathyroidism and two affected males and one affected female, with the neurodevelopmental disorder. It appeared that skewed X-inactivation in the female carriers was responsible for the different phenotypic features. The association between ZFX variants and a novel neurodevelopmental disorder, was further supported by functional studies showing altered transcriptional activity in missense variants and altered behavior in a zebrafish loss-of-function model. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v5.402 | ACBD6 |
Arina Puzriakova edited their review of gene: ACBD6: Added comment: - PMID: 21937992 (2011) - single individuals with a p.G22fs variant in the ACBD6 gene, presenting with mild ID, microcephaly, facial dysmorphism, spasticity. Limited additional information. - PMID: 32108178 (2020) - two unrelated individuals with neurodevelopmental disorder (moderate ID is noted but otherwise limited clinical information) and carrying homozygous LoF variants in the ACBD6 gene (1 frameshift, 1 canonical splice). One individual also carried an allelic homozygous variant in the PRDX6 gene (unlikely but unknown disease consequence). Skin-derived patient fibroblasts showed reduced ACBD6 expression and N-myristoylation deficiency. - PMID: 36457943 (2023) - two Thai siblings presenting with profound ID, morbid obesity, pancytopenia with severe recurrent infections, diabetes mellitus, cirrhosis, and renal failure, leading to deaths in their early 30s. Sequencing showed a novel homozygous single bp duplication (c.360dup; p.Leu121Thrfs*27) in the ACBD6 gene. Parents were heterozygous carriers. - PMID: 37951597 (2023) - 45 previously undiagnosed individuals from 28 families with a neurodevelopmental syndrome including a complex and progressive movement disorder phenotype. Cardinal clinical features include moderate-to-severe GDD/ID (45/45), facial dysmorphism (38/40), HC <2nd percentile (21/31), weight >50th percentile (20/34), mild cerebellar ataxia (35/41), limb spasticity/hypertonia (31/41), gait abnormalities (33/35), dystonia (30/32) and variable epilepsy (13/29). Homozygous ACBD6 variants were identified by WES in all cases, including 18 predicted LoF, 1 missense and 1 inframe insertion. Knockout studies in zebrafish recapitulate clinical features reported in patients such as movement disorders, seizures, and facial dysmorphology, while inactivation of acbd6 in X. tropicalis predominantly caused embryo death while surviving tadpoles demonstrated microcephaly, reduced movement, eye abnormalities, and brain structure differences.; Changed rating: GREEN; Changed publications to: 21937992, 32108178, 36457943, 37951597; Changed phenotypes to: Neurodevelopmental disorder, MONDO:0700092; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v5.222 | PIP5K1C |
Achchuthan Shanmugasundram gene: PIP5K1C was added gene: PIP5K1C was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: PIP5K1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PIP5K1C were set to 37451268 Phenotypes for gene: PIP5K1C were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071 Review for gene: PIP5K1C was set to GREEN Added comment: Three de novo heterozygous missense variants in PIP5K1C (p.Glu146Lys, p.Tyr205Cys & p.Tyr221Cys) were identified in nine unrelated children exhibiting intellectual disability, developmental delay, acquired microcephaly, seizures, visual abnormalities, and dysmorphic features. Intellectual disability was reported in all nine children and seizures were present in seven children, of which three had developmental and epileptic encephalopathy. In addition, there is functional evidence available, which includes an in vivo zebrafish model that recapitulates the human phenotype (developmental defects affecting the forebrain, including the eyes, as well as craniofacial abnormalities) (PMID:37451268). This gene has been associated with another phenotype (Lethal congenital contractural syndrome 3, MIM #611369) in both OMIM and Gene2Phenotype, but not yet associated with this neurodevelopmental disorders in either databases. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.96 | CTR9 |
Achchuthan Shanmugasundram edited their review of gene: CTR9: Added comment: As noted by the reviewer, PMID: 35499524 reported 13 unrelated cases identified with heterozygous variants in CTR9 gene (11 different variants) and they presented with overlapping neurodegenerative phenotypes including intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. The intellect levels were determined only for 11 patients (the rest are too young) and 8 out of these 11 patients were reported with variable degree of intellectual disability, while other three had impairments in other domains or learning difficulties. PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in zebrafish also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum). This gene has not yet been associated with relevant phenotypes in OMIM. It has been associated with Wilms tumour in Gene2Phenotype (phenotype not relevant to this panel).; Changed rating: GREEN; Changed publications to: 35499524, 35717577 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.94 | CTR9 |
Achchuthan Shanmugasundram changed review comment from: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum). This gene has not yet been associated with relevant phenotypes in OMIM. It has been associated with Wilms tumour in Gene2Phenotype (phenotype not relevant to this panel).; to: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in zebrafish also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum). This gene has not yet been associated with relevant phenotypes in OMIM. It has been associated with Wilms tumour in Gene2Phenotype (phenotype not relevant to this panel). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.93 | DPYSL2 |
Achchuthan Shanmugasundram changed review comment from: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients. PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus. It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype. Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability. Sources: Literature; to: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients. PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus. It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype. Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v4.93 | DPYSL2 |
Achchuthan Shanmugasundram gene: DPYSL2 was added gene: DPYSL2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: DPYSL2 were set to 27249678; 35861646 Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071; Aplasia/Hypoplasia of the corpus callosum, HP:0007370 Review for gene: DPYSL2 was set to AMBER Added comment: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients. PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus. It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype. Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1576 | PRPF8 |
Konstantinos Varvagiannis gene: PRPF8 was added gene: PRPF8 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PRPF8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRPF8 were set to 35543142 Phenotypes for gene: PRPF8 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Retinitis pigmentosa 13, MIM # 600059 Penetrance for gene: PRPF8 were set to unknown Review for gene: PRPF8 was set to AMBER Added comment: A recent study suggests that heterozygous PRPF8 variants are associated with a syndromic form of DD/ID, in some cases epilepsy with heterogeneous other clinical findings. However the authors acknowledge that not all variants within their cohort may be pathogenic (5 VUSs using ACMG criteria) and that conclusive evidence may necessitate functional studies. Heterozygous variants (typically clustering in exon 42) have been reported to cause a non-syndromic form of RP with variable expressivity and incomplete penetrance (Retinitis pigmentosa 13, MIM # 600059) . Overall consider inclusion with amber rating. ------ O'Grady et al. (2022 - PMID: 35543142) describe the phenotype of 14 unrelated individuals with heterozygous, mostly de novo, missense and pLoF variants in PRPF8. Nearly all had some degree of global developmental delay or ID (13/14). 6/14 had a diagnosis of ASD. Seizures were reported in 4 or 5 subjects. Other features included short stature (6/14), abnormal gait, cardiac anomalies and somewhat overlapping facial features (11/14). Ages ranged from 4 - 19 years (median : 9y). PRPF8 encodes a component of the spliceosomes which in turn are involved in removal of introns from mRNA precursors. The gene is ubiquitously expressed with expression within brain being highest in cerebral cortex, basal ganglia and cerebellum (Refs. provided). Individuals were investigated with exome sequencing (12/14) or an autism/ID panel of >2500 genes (likely application of virtual panel on exome data). 13 individuals harbored a missense SNV and 1 further had a frameshift variant. In 12 individuals the variant had occurred de novo. 1 individual had inherited the variant from a possibly mosaic parent, while for 1 further a single parental sample was available. PRPF8 is intolerant to both missense (Z = 8.28) and pLoF variants (pLI : 1). Variants in 5 individuals were formally classified as VUS while 2 variants were present in gnomAD. Additional findings (CNVs/SNVs) were reported, in some cases possibly of relevance. As the authors discuss, heterozygous pathogenic missense SNVs cause (and account for ~2-3% of) non-syndromic AD retinitis pigmentosa with variable expressivity and incomplete penetrance. Variants for this phenotype are typically missense - although nonsense ones have also been reported - clustering within ex42 (of 43) encoding the MPN domain (aa 2103-2335 / NP_006436) and weakening interaction with 2 other spliceosomal proteins. Variants in the present study occurred throughout the gene. Although not universally assessed within the cohort, only one participant had RP (in this case variant within the MPN domain). There were no variant studies performed. Animal models: the authors cite a study by Graziotto et al (2011 - PMID: 20811066) where knock-in mice for a missense variant in ex42 displayed defects of the retinal pigment epithelium. A zebrafish ko model also cited (Keightley et al, 2013 - PMID: 23714367) displayed widespread apoptosis in brain and spinal cord. The authors cite a previous bioinformatic study identifying PRPF8 as a major hub connecting gene-interaction networks for NDDs (Casanova et al, 2018 - PMID: 30420816) as well as 2 studies demonstrating enrichment of variants in individuals with NDDs compared to controls (da Silva Montenegro et al, 2020 - PMID: 31696658, Karczewski et al, 2020 - PMID: 32461654). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1562 | CTR9 |
Konstantinos Varvagiannis gene: CTR9 was added gene: CTR9 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CTR9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTR9 were set to 35499524; 2815719; 25363760; 27479843; 25099282; 29292210 Phenotypes for gene: CTR9 were set to Delayed speech and language development; Motor delay; Intellectual disability; Behavioral abnormality; Autistic behavior; Failure to thrive; Feeding difficulties; Abnormality of the cardiovascular system Penetrance for gene: CTR9 were set to unknown Mode of pathogenicity for gene: CTR9 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: CTR9 was set to AMBER Added comment: Meuwissen, Verstraeten, Ranza et al (2022 - PMID: 35499524) describe the phenotype of 13 unrelated individuals harboring heterozygous - predominantly de novo - CTR9 missense variants. Overlapping features included delayed speech and/or motor development (each in 9 cases) with the latter complicated by hypotonia or hyperlaxity in some cases. Balance or coordination problems were also reported in some. Variable degrees of ID ranging from mild to severe were observed in all individuals of relevant age except for 3 who however experienced impairment in other domains and/or learning difficulties (8/11 - 2 individuals were too young for evaluation). Few had evidence of regression. Other features included behavioral abnormalities (incl. ASD in 4), FTT/feeding problems (in 5), cardiovascular findings (in 4 - incl. infantile thoracic aortic aneurysm, VSD, pulm. valve stenosis, SVAS). The authors reported variable/nonspecific dysmorphic features. WES revealed heterozygous CTR9 missense variants in all cases (NM_014633.5 as RefSeq). The variants occurred de novo in most (11/13) individuals with a one proband having inherited the variant from his affected parent. For one case, a single parental sample was available. Most SNVs were absent from gnomAD with the exception of c.1364A>G/p.Asn455Ser and c.2633G>A/p.Arg878Gln present once in the database (Z-score for CTR9: 4.3 / pLI : 1). The variants affected highly conserved residues with in silico predictions mostly in favor of a deleterious effect. CTR9 encodes a subunit of the PAF1 complex (PAF1C) with the other subunits encoded by PAF1, LEO1, CDC73, RTF1 and WDR61/SKI8. The complex acts as a transcriptional regulator with CTR9 binding RNA polymerase II. The complex influences gene expression by promoting H2BK123 ubiquitylation, H3K4 and H3K36 methylation. In yeast, Paf1 and Ctr9 appear to mediate involvement of Paf1C in induction of mitophagy (several Refs provided). In silico modeling: a group of N-terminal variants likely destabilize structure, another group possibly perturbs CTR9-PAF1 interactions and a 3rd class influences interactions with other subunits. p.Glu15Lys did not appear to influence protein stability. Functional studies: H3K4/H3K36 methylation analysis, mitochondrial quality assessment and RNA-seq studies in fibroblasts did not provide conclusive evidence for downstream consequences of the variants (albeit a brain-specific effect - as demonstrated for other disorders – cannot be excluded). Animal models: In zebrafish, the Paf1C complex has been shown to play a role in cardiac specification and heart morphogenesis with ctr9 mutants showing severe defects in morphogenesis of primitive heart tube (cited PMID: 21338598). This supports a role of the CTR9 variants in the cardiac abnormalities observed in 4 individuals. Although Paf1C zebrafish homologues are required for Notch-regulated transcription (cited PMID: 17721442), there was no supporting evidence from RNA-seq analyses performed by the authors. In Drosophila, Ctr9 has a key role at multiple stages of nervous system development in Drosophila (cited PMID: 27520958). In rat, Ctr9 is expressed in dopaminergic neurons, with its expression not restricted to the nucleus, regulating dopamine transporter activity (cited PMID: 26048990). As commented, de novo CTR9 variants have been identified in indivdiduals with developmental disorders in larger cohorts, though without phenotypic details (DDD study - PMID:2815719, De Rubeis et al, 2014 - PMID: 25363760, Lelieveld et al PMID: 27479843) [ https://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=CTR9 ] Two previous studies (Hanks et al, 2014 - PMID: 25099282, Martins et al 2018, PMID: 29292210) have identified individuals with pLoF variants [in almost all cases leading to skipping of ex9 e.g. NM_014633.4:c.958-9A>G or (RefSeq not provided) c.1194+2T>C, c.1194+3A>C, the single exception being c.106C>T/p.Q36*] in individuals and families with Wilms tumor after exclusion of other genetic causes. Analyses of tumor samples revealed in several of these cases either LOH (most commonly) or truncating variants as second hits. These individuals did not display neurodevelopmental phenotypes (despite detailed clinical information provided in the 2 studies). CTR9 is included in the gene panels for WT and Tumor predisposition - childhood onset with green rating. [In addition few individuals with hyperparathyroidism jaw tumor syndrome due to heterozygous variants in CDC73 - another subunit of the PAF1 complex - have been reported with WT]. Given these reports, commenting on the embryonic lethality of Ctr9 homozygous ko mice (MGI) and the observation of only missense variants in their cohort Meuwissen, Verstraeten, Ranza et al presume that a dominant-negative effect may apply for the variants they report. Consider inclusion in the current panel with amber (variant effect/underlying mechanism unknown) or green rating (>3 individuals/families/variants, multiple reports, some supporting evidence from animal models). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1561 | CDK9 |
Konstantinos Varvagiannis changed review comment from: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent. CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4]. Animal models also provide some supporting evidence [discussed Ref4]. Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below. [1]----- Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity. After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing. Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630). Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect. Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype. [2]----- Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys. All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3. [3]----- Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID. In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal. All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect. The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2. In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas). [4]----- Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia. Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect. In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2). The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824). Sources: Literature; to: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent. CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4]. Animal models also provide some supporting evidence [discussed Ref4]. Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below. [1]----- Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance due to consanguinity. Using autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing. Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630). Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect. Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in one case). Overall, the authors used the term CHARGE-like for this phenotype. [2]----- Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys. All presented a CHARGE-like phenotype with ophthalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two of them), heart defect (2/3 with VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags in 2/3, bilateral deafness 1/3, bilateral ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3. [3]----- Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID. In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 | suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal. All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with several in silico tools in favor of a deleterious effect. The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacting with AF4/FMR2. In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas). [4]----- Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia. Trio exome revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect. In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2). The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited : 27715402, 30100824). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1561 | CDK9 |
Konstantinos Varvagiannis gene: CDK9 was added gene: CDK9 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CDK9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK9 were set to 26633546; 30237576; 29302074; 33640901 Phenotypes for gene: CDK9 were set to Global developmental delay; Intellectual disability; Abnormality of vision; Congenital cataract; Iris coloboma; Abnormal heart morphology; Choanal atresia; Abnormality of the ear; Preauricular skin tag; Hearing impairment; Abnormality of the genitourinary system; Abnormality of limbs; Abnormality of the vertebrae; Abnormality of nervous system morphology; Seizures Penetrance for gene: CDK9 were set to Complete Review for gene: CDK9 was set to GREEN Added comment: There are 4 studies reporting on the phenotype associated with biallelic CDK9 pathogenic variants. DD and ID are part of the phenotype which appears to be relatively consistent. CDK9 encodes Cyclin-dependent kinase 9. There are 4 missense variants reported to date - one of which recurrent (NM_001261.3:c.673C>T / p.Arg225Cys) - with studies for 3 variants suggesting a LoF effect (loss of kinase activity) [Ref4]. Animal models also provide some supporting evidence [discussed Ref4]. Consider inclusion in the current panel (probably with green rating) as well as other possibly relevant ones. Details provided below. [1]----- Shaheen et al (2016 - PMID: 26633546) studied patients with apparently novel phenotypes with positive family history consistent with AR inheritance mode due to consanguinity. After autozygome analysis the authors determined the shared autozygome (ROH >1 Mb / Axiom SNP Chip) in families with multiple affected individuals. This analysis was followed by whole exome/genome sequencing. Using this approach, they managed to map the phenotype of interest to a single novel locus in some families, which was also the case in a large consanguineous family with 2 similarly affected cousins (11DG0424, 11DG1630). Within a 20 Mb region of homozygosity, followed by WES in a single affected individual and Sanger confirmation with compatible segregation studies in parents and 10 unaffected sibs, the authors identified a homozygous CDK9 missense SNV (NM_001261.3:c.673C>T / p.Arg225Cys) responsible for this phenotype. In silico predictions were concordant in favor of a deleterious effect. Features (detailed in the suppl.) included global DD (2/2), severe ID (1/1), cerebral and (mild) cerebellar atrophy (2/2), microcephaly (2/2), ocular anomalies (2/2, coloboma in 2/2, congenital cataract 2/2, etc), heart defects (2/2, PDA in both, ASD), variable genitourinary anomalies (2/2 incl. hydronephrosis, VUR reflux/recurrent UTIs, kidney atrophy, abn. genitalia in 1), abnormalities of the limbs (2/2, bilateral talipes equinovarus : 2/2) or the skeleton (1/2 - butterfly vertebrae). One was reported to have some degree of growth delay (<10th centile for length, <5th for weight and OFC). There was no hearing defect reported (large ears in 1/2). Overall, the authors used the term CHARGE-like phenotype. [2]----- Maddirevula et al (2019 - PMID: 30237576) performed autozygome and exome analysis of individuals with suspected Mendelian disorders. They reported 3 individuals (18DG0161, 18DG0162, 18DG0165) born to 3 different consanguineous families (information in fig2) from Qatar, homozygous for CDK9 p.Arg225Cys. All presented a CHARGE-like phenotype with features ophtalmologic findings (3/3 - abnormal ERG in one, congenital cataracts the other, visual impairment in the 3rd, though NO evidence of coloboma in at least two), heart defect (2/3 had VSD), choanal atresia (3/3), retarded growth/FTT (1/3) or global DD (3/3 - in suppl. table 1), (genito)urinary anomalies (1/3 - dysplastic atrophic kidney) or ear anomalies (3/3 - preauricular tags 2/3, bilateral deafness 1/3, bilat.ossicular anomalies 1/3). Other features incl. epilepsy (2/3), brain MRI abnormalities (2/3), facial asymmetry in one, vertebral segmentation defect in 1/3. [3]----- Hu et al (2019 - PMID: 29302074) performed WES/WGS in 404 consanguineous families from Iran, having 2 or more offspring with ID. In this context they reported 2 females and a male (III:1,4,3 belonging to fam. M9100018 - details in suppl. text) born to first cousin parents from Iran. Features included DD (3/3 - walking at 3y, words at 4y), moderate ID (3/3 - WAIS-IV IQ of 40-43), short stature (3/3 below 3rd %le). Vision and hearing were normal. All three were homozygous for a missense SNV (NM_001261:c.280C>T, p.Arg94Cys) which was ultrarare in ExAC, with severa in silico tools in favor of a deleterious effect. The authors commented that CDK9 is the catalytic core of transcription elongation factor p-TEFb essential for transcription elongation of numerous genes, Cdk9/Cyclin T1 complex may participate in neuronal differentiation, CDK9-cyclinK in maintenance of genomic integrity, with the protein encoded also interacted with AF4/FMR2. In addition the gene was commented to have ubiquitous expression with high protein expression in glial and neuronal cells of the cortex (based on Uniprot and Human Protein Atlas). [4]----- Nishina et al (2021 - PMID: 33640901) described an 8 y.o. male with facial asymmetry, ear/hearing anomalies (microtia, preauricular tags, bilateral hearing loss), ocular/vision anomalies (blepharophimosis, lacrimal obstruction, eyelid dermoids, duane-like anomaly, congenital cataracts, retinal dystrophy), cleft lip and palate, abnormalities of the limbs (finger contractures with associated absence of creases, cutaneous syndactyly, etc). Other features included cardiac dysrhythmia and undescended testes. Development was delayed with associated ID (walking 3y, words 7y, at 10y: could count to 20, 4 word sentences). There was no evidence of coloboma or choanal atresia. Trio exome sequencing revealed that the child was compound htz for 2 missense SNVs (NM_001261.3:c.862G>A / p.Ala288Thr and c.907C>T /p.Arg303Cys) with Sanger confirmation. These were ultrarare/not present in gnomAD. Both lied in the protein kinase catalytic domain of CDK9, with high conservation across different species and in silico predictions in favor of deleterious effect. In vitro studies in HEK293 cells demonstrated that the kinase activity for both variants was significantly reduced compared to wt. Kinase activity was also reduced for the Arg225Cys variant (reported in Refs 1 & 2). The authors briefly discuss evidence from zebrafish (regulates larval morphogenesis incl. brain, heart, eye, blood vessels) and mouse models. In the latter complete LoF is lethal while heterozygous LoF is associated with abnormal morphology of heart, skin and epididymis (PMIDs cited by the authors : 27715402, 30100824). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1520 | HIST1H4D |
Konstantinos Varvagiannis gene: HIST1H4D was added gene: HIST1H4D was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HIST1H4D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HIST1H4D were set to 35202563 Phenotypes for gene: HIST1H4D were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face Penetrance for gene: HIST1H4D were set to Complete Mode of pathogenicity for gene: HIST1H4D 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: HIST1H4D was set to AMBER Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair. There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues. Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes). Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern : - H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563), - H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563), - H4C4/HIST1H4D (1 subject - PMID:35202563), - H4C5/HIST1H4E (17 subjects - PMID: 35202563), - H4C6/HIST1H4F (1 subject - PMID: 35202563), - H4C9/HIST1H4I (3 subjects - PMID: 35202563). Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall). Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth). Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression). Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one. Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes. Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green. Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc). ------ Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent]. Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3). Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature). RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle). Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant. Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied. ------ In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above). ------ Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely: - H4C3 (HIST1H4C/N=6 subjects), - H4C11 (HIST1H4J/N=1), - H4C4 (HIST1H4D/N=1), - H4C5 (HIST1H4E/N=17), - H4C6 (HIST1H4F/N=1), - H4C9 (HIST1H4I/N=3). All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors). The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER. Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents. Previous work-up or presence of additional variants are not discussed. At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones. There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys). All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited). Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11). For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants. H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants. ------ [RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala] Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1520 | HIST1H4E |
Konstantinos Varvagiannis gene: HIST1H4E was added gene: HIST1H4E was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HIST1H4E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HIST1H4E were set to 35202563 Phenotypes for gene: HIST1H4E were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face Penetrance for gene: HIST1H4E were set to unknown Mode of pathogenicity for gene: HIST1H4E 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: HIST1H4E was set to GREEN Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair. There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues. Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes). Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern : - H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563), - H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563), - H4C4/HIST1H4D (1 subject - PMID:35202563), - H4C5/HIST1H4E (17 subjects - PMID: 35202563), - H4C6/HIST1H4F (1 subject - PMID: 35202563), - H4C9/HIST1H4I (3 subjects - PMID: 35202563). Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall). Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth). Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression). Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one. Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes. Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green. Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc). ------ Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent]. Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3). Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature). RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle). Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant. Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied. ------ In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above). ------ Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely: - H4C3 (HIST1H4C/N=6 subjects), - H4C11 (HIST1H4J/N=1), - H4C4 (HIST1H4D/N=1), - H4C5 (HIST1H4E/N=17), - H4C6 (HIST1H4F/N=1), - H4C9 (HIST1H4I/N=3). All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors). The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER. Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents. Previous work-up or presence of additional variants are not discussed. At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones. There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys). All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited). Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11). For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants. H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants. ------ [RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala] Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1520 | HIST1H4F |
Konstantinos Varvagiannis gene: HIST1H4F was added gene: HIST1H4F was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HIST1H4F was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HIST1H4F were set to 35202563 Phenotypes for gene: HIST1H4F were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face Penetrance for gene: HIST1H4F were set to unknown Mode of pathogenicity for gene: HIST1H4F 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: HIST1H4F was set to AMBER Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair. There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues. Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes). Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern : - H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563), - H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563), - H4C4/HIST1H4D (1 subject - PMID:35202563), - H4C5/HIST1H4E (17 subjects - PMID: 35202563), - H4C6/HIST1H4F (1 subject - PMID: 35202563), - H4C9/HIST1H4I (3 subjects - PMID: 35202563). Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall). Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth). Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression). Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one. Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes. Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green. Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc). ------ Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent]. Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3). Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature). RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle). Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant. Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied. ------ In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above). ------ Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely: - H4C3 (HIST1H4C/N=6 subjects), - H4C11 (HIST1H4J/N=1), - H4C4 (HIST1H4D/N=1), - H4C5 (HIST1H4E/N=17), - H4C6 (HIST1H4F/N=1), - H4C9 (HIST1H4I/N=3). All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors). The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER. Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents. Previous work-up or presence of additional variants are not discussed. At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones. There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys). All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited). Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11). For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants. H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants. ------ [RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala] Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1520 | HIST1H4I |
Konstantinos Varvagiannis gene: HIST1H4I was added gene: HIST1H4I was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HIST1H4I was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: HIST1H4I were set to 35202563 Phenotypes for gene: HIST1H4I were set to Global developmental delay; Intellectual disability; Microcephaly; Growth abnormality; Abnormality of the face Penetrance for gene: HIST1H4I were set to unknown Mode of pathogenicity for gene: HIST1H4I 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: HIST1H4I was set to GREEN Added comment: Histone H4 is a core component of the nucleosome, the basic repeating unit of eukaryotic chromatin. Each nucleosome consists of ~150 bp of DNA wrapped around a histone octamer. Each histone octamer is composed of 2 copies of each of the histones H2A, H2B, H3, H4. This organization is important for DNA replication, transcription and repair. There are 14 canonical histone H4 genes in the human genome, which despite being different at the nucleotide level encode an identical protein. These cluster in 3 genomic loci. Their transcription is independently regulated with differing expression during brain development and in human tissues. Histone H4 forms a dimer with H3 (which however has variant isoforms linked to specific cellular processes). Pathogenic variants in genes encoding H4 have been reported in several individuals. Irrrespective of the gene for H4 involved, all patients presented with highly overlapping features, DD and ID being universal. Available reports to date concern : - H4C3/HIST1H4C (9 subjects - PMID: 28920961, 35202563), - H4C11/HIST1H4J (1 subject - PMID: 31804630, 35202563), - H4C4/HIST1H4D (1 subject - PMID:35202563), - H4C5/HIST1H4E (17 subjects - PMID: 35202563), - H4C6/HIST1H4F (1 subject - PMID: 35202563), - H4C9/HIST1H4I (3 subjects - PMID: 35202563). Variants in all cases were missense SNVs, occurring (in almost all cases) as dn variants and affecting the same residue in the same and/or different H4 genes (details for clusters below). Eg. Arg45Cys was a recurrent variant for H4C5 (>=7 subjects), while variants affecting Arg40 have been reported in H4C4, H4C5, H4C9, H4C11 (7 subjects overall). Zebrafish studies for all genes reported have included most - if not all - patient variants and recapitulate features observed in affected individuals (head size/structure and growth). Additional studies specificaly for H4C3/HIST1H4C have been performed in patient fibroblasts (demonstrating among others transcriptional dysregulation) and zebrafish (accumulation of DSBs, increased apoptosis in head/tail, abn. cell cycle progression). Note that the nomenclature for variants - at the protein level - used in literature commonly takes into consideration cleavage of Met1, thus the numbering may not correspond to the HGVS one. Relevant entries exist in OMIM, G2P and SysID only for H4C3/HIST1H4C (Tessadori-van Haaften neurodevelopmental syndrome 1, #619758) and H4C11/HIST1H4J (?Tessadori-van Haaften neurodevelopmental syndrome 2, #619759) but not for other genes. Rating in PanelApp Australia - ID Panel : HIST1H4C Green, H4J Amber, H4D Amber, H4E Green, H4F Amber, H4I Green. Please consider inclusion in other possibly relevant panels (microcephaly, short stature/FTT, etc). ------ Initial work from Tessadori et al (incl. DDD study, 2017 - PMID:28920961) identified monoallelic missense SNVs affecting the same residue of H4C3 (HIST1H4C), in 3 individuals from 2 families. [c.274A>C/ HGVS p.(Lys92Gln) dn in 1 subject and c.275A>C/ HGVS p.(Lys92Arg) inherited from unaffected mosaic parent]. Individuals from both families having relevant age had intellectual disability (2/2 - 2 families). Other features incl. growth delay (3/3) and microcephaly (3/3). Expression of the variants in zebrafish severely affected structural development recapitulating the patient phenotypes (microcephaly and short stature). RNA sequencing in fibroblasts from 2 unrelated patients and a control, revealed that expression of H4C3 variants was similar to wt. The authors estimated that ~8% of H4 cDNA molecules contained the variant. LC-MS/MS analysis suggested that the mutant protein was present in nucleosomes at a level of 1-2% while RNA-seq identified 115 differential expressed genes, with enrichment for relevant procedures (chr. organization, histone binding, DNA packaging, nucleosomal organization, cell cycle). Post-translational modifications of Lys92 (H4K91) are highly conserved and have been previously associated with processes from chromatin assembly , DNA damage sensitivity, etc. Post-translational marks on Lys92 (K91) were absent in patient derived cells as a result of each variant. Zebrafish models for both variants were suggestive for accumulation of double strand breaks (DSBs) more visible in heads and tails of larvae. Embryos expressing mutants displayed increased apoptosis in head and tail. Additional studies in larvae were suggestive of abnormal cell cycle progression (rel. increase in cellls in S/G2/M phase, increased occurrence of activated CHK2 with p53 stabilization) applying to both variants studied. ------ In a subsequent publication, Tessadori et al. (2020 - PMID: 31804630) described the phenotype of a 14 y.o. boy harboring a dn heterozygous missense H4C11 (HIST1H4J) variant following trio-ES [c.274A>G / HGVS p.(Lys92Glu)]. Features incl. profound ID, microcephaly, short stature with some dysmorphic features (uplsanting p-f, hypertelorism, etc). Previous work-up was normal/non-diagnostic and incl. FMR1, MECP2 and a CMA showing an inherited 207 kb CNV involving KCNV1. Upon mRNA microinjection in zebrafish embryos - either for wt or for Lys92Glu HIST1H4J - effect for wt was very mild. Lys92Glu expression led to defective development of head structures (brain, eyes), faulty body axis growth and dysmorphic tail reproducing the microcephaly and short stature phenotype. This was similar to previous zebrafish studies for HIS1H4C variants (above). ------ Tessadori et al. (2022 - PMID: 35202563) describe 29 *additional individuals with de novo missense variants in genes encoding H4, namely: - H4C3 (HIST1H4C/N=6 subjects), - H4C11 (HIST1H4J/N=1), - H4C4 (HIST1H4D/N=1), - H4C5 (HIST1H4E/N=17), - H4C6 (HIST1H4F/N=1), - H4C9 (HIST1H4I/N=3). All individuals, exhibited DD and ID (29/29). Other features incl. hypotonia (10/29), seizures (5/29), autism (5/29), ataxia (4/29). Abnormal growth incl. progressive microcephaly (2/19 prenatal, 20/29 postnatal onset), short stature/FTT (each 11/29). Few had skeletal features (craniosynostosis 2/29, abn. digits 4/29, vertebral 4/29). Some had visual (17/28) or hearing impairment (7/29). Facial features incl. hypertelorism (5/29), upslanting p-f (3/29), broad nasal tip (11/29), thin upper lip (4/29) and teeth anomalies (6/29 - notably gap between central incisors). The authors state that the cohort was collected with trio WES but also after data sharing via Genematcher / DECIPHER. Identified variants were in all cases missense and de novo, the latter either by trio WES or Sanger sequencing of parents. Previous work-up or presence of additional variants are not discussed. At the protein level 10 aa were affected, 6 of which recurrently within the same gene (Arg45, His75, Lys91, Tyr98) as well among several genes for H4 (Pro32, Arg40). Variants lied within two clusters, one corresponding to the α-helix of H4 (reported variants affected Lys31 - Arg45) important for DNA contacts, interactions with H3 and histone chaperones. The other within the core of nucleosome (reported patient variants : His75-Tyr98) with important strucural contact between H3-H4 dimer and histone chaperones. There were no detectable genotype-phenotype patterns separating individual H4 genes or protein regions. Of note, variability was observed even among 7 individuals with the same dn H4C5 variant (Arg45Cys). All variants were absent from control databases incl. gnomAD and affected residues conserved through to S. cerevisiae. Substitutions affecting Arg45 and Gly94 and His75 have been studied previously with effect in growth/fitness/chromatin remodeling/DNA damage repair depending on variant (5 studies cited). Zebrafish embryos at the 1 cell stage were injected with mRNA encoding either wt or identified variants, the latter inducing significant developmental defects with the exception of Pro32Ala (H4C3) and Arg40Cys (H4C5, H4C11). For Pro32Ala and Arg40Cys however, the strong recurrence in this cohort supports pathogenicity. A dosage dependent effect was observed for 2 variants. H4 genes appear to be tolerant to both missense and loss-of-function variation (the latter even in homozygous form) suggesting a dominant effect of the variants. ------ [RefSeqs : H4C3/HIST1H4C - NM_0035242.4 | H4C4/HIST1H4D - NM_003539.4 | H4C5/HIST1H4E - NM_003545.3 | H4C6/HIST1H4F - NM_003540.4 | H4C9/HIST1H4I - NM_003495.2 | H4C11/HIST1H4J - NM_021968.4 // Variants at the protein level above are according to the HGVS nomenclature. However as the N-terminal methionine is cleaved, numbering relative to the mature peptide has also been used in publications eg. p.Pro33Ala HGVS corresponding to Pro32Ala] Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1518 | NRCAM |
Konstantinos Varvagiannis gene: NRCAM was added gene: NRCAM was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NRCAM were set to 35108495 Phenotypes for gene: NRCAM were set to Hypotonia; Hypertonia; Spasticity; Global developmental delay; Intellectual disability; Microcephaly; Behavioral abnormality; Neuropathy; Hearing abnormality; Abnormality of the eye; Abnormality of the skeletal system; Scoliosis; Abnormality of the face Penetrance for gene: NRCAM were set to Complete Review for gene: NRCAM was set to GREEN Added comment: Kurolap et al (2022 - PMID: 35108495) describe the phenotype of 10 individuals (from 8 families) with biallelic variants in NRCAM. Features included tone abnormalities (hypotonia in 4/10, hypertonia/spasticity in 4/10), DD (8/10 - 7 families) and cognitive impairment (in 7/10 - 6 fam), neuropathy (4/10 - incl. 2 sibs without DD/ID). Other phenotypes incl. FTT (2/8), microcephaly (3/6), variable behavioral issues (3/5), abnormalities from the eyes/vision (6/8 - cataract in 2), abnormal hearing (3/7) or skeletal findings (8/9 - incl. scoliosis in 5). Nonspecific facial features were reported in 5/8. Previous metabolic, genetic (incl. karyotype or CMA, FMR1, testing for Steinert disease or SMA) or other work-up (e.g. muscle biopsy) is reported for several subjects but was normal/non-diagnostic. All were investigated by WES/WGS which revealed biallelic NRCAM variants. Sanger sequencing was used for confirmation and segregation analyses, with compatible results in several affected/unaffected sibs tested. There were no alternative explanations for the NDD phenotype with the exception of one subject with a mosaic functionally characterized LP KRAS variant suspected to contribute to his phenotype. NRCAM encodes neuronal cell adhesion molecule (CAM). CAMs are membrane bound proteins with important role in tissue morphogenesis and maintenance. They mediate interactions between neighboring cells or cells and the extracellular matrix. The L1 subgroup of immunoglobulin CAMS - consisting of L1CAM, neurofascin, NRCAM, CHL1 - is the most abundant in the CNS with several critical functions in CNS development, among others in neural cell differentiation, axonal growth and guidance, myelination, synapse formation. Pathogenic L1CAM (XL) and NFASC variants (AR) are associated with NDD. Different missense (N=7), stopgain/frameshift (N=3), a splice variant (NM_001037132.2:c.2647-2A>G) as well as a deep intronic one (c.230+824G>C / rs575851831). Variants occurred in different domains with a cluster (42%) in the fibronectin III domain. Missense SNVs were ultrarare or not present in gnomAD, occurred in conserved residues, with several in silico predictions in favor of a deleterious effect. Structural modelling suggested that all substitutions occurred at residues exposed to solvent and possible abrogated interaction with other proteins. There were no expression studies performed at the mRNA/protein level. The splice variant is predicted to cause ex22 skipping leading to frameshift. The deep intronic variant is predicted to disrupt a site for spl. regulator SC35 and may cause activation of a cryptic acceptor site with inclusion of a cryptic exon. The zebrafish nrcama gene is the sole ortholog of human NRCAM, with another gene proposed as possible ortholog (nrcamb) mapping upon BLAST analysis to cntn1a. The authors performed CRISPR-Cas9 mutagenesis in zebrafish introducing a partial deletion of ex18 and 19. Mutant zebrafish were viable, displayed altered axonal projections and abnormal swimming behavior (increased movement in darkness). Currently, there is no NRCAM-associated phenotype in OMIM/G2P/SysID. PanelApp Australia includes NRCAM in its ID panel with green rating. Consider inclusion probably with green (>3 individuals/families/variants, segregation, gene in the L1-Ig CAM family causing NDD, zebrafish model) or amber rating (ID not a universal feature, variant effect not studied). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1220 | VPS50 |
Konstantinos Varvagiannis gene: VPS50 was added gene: VPS50 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to 34037727 Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum Penetrance for gene: VPS50 were set to Complete Review for gene: VPS50 was set to AMBER Added comment: Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants. Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging. Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)). VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor. As discussed by Schneeberger et al (refs provided in text): - VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development. - Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality. Studies performed by Schneeberger et al included: - Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del). - Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels. - Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts. - Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function. As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders". There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes. Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1216 | AP1G1 |
Zornitza Stark gene: AP1G1 was added gene: AP1G1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: AP1G1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: AP1G1 were set to 34102099 Phenotypes for gene: AP1G1 were set to Neurodevelopmental disorder (NDD); Intellectual Disability; Epilepsy Review for gene: AP1G1 was set to GREEN gene: AP1G1 was marked as current diagnostic Added comment: Two bi-allelic homozygous missense variants were found in two distinct families with Italian and Pakistani origins; homozygous missense variants. Eight de novo heterozygous variants were identified in nine isolated affected individuals from nine families; including five missense, two frameshift, and one intronic variant that disrupts the canonical splice acceptor site. Knocking out AP1G1 Zebrafish model resulted in severe developmental abnormalities and increased lethality. All individuals had neurodevelopmental disorder (NDD) including global developmental delay and ID, which varied in severity from mild to severe. GREEN for mono-allelic, AMBER for bi-allelic. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.644 | BICRA |
Zornitza Stark gene: BICRA was added gene: BICRA was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: BICRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BICRA were set to 33232675 Phenotypes for gene: BICRA were set to Developmental delay, intellectual disability, autism spectrum disorder,behavioral abnormalities, dysmorphic features Review for gene: BICRA was set to GREEN Added comment: 12 individuals reported, 11 de novo (1 not resolved), with neurodevelopmental phenotypes—developmental delay (HP:0001263), intellectual disability (HP:0001249), autism spectrum disorder (HP:0000729), and/or behavioral phenotypes (HP:0000708)—and variable structural birth defects and dysmorphic features. Mostly LoF or gene deletions, but 2 missense reported. Zebrafish model supports the gene-disease association. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.500 | AGAP1 |
Zornitza Stark gene: AGAP1 was added gene: AGAP1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: AGAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AGAP1 were set to 31700678; 25666757; 30472483 Phenotypes for gene: AGAP1 were set to Cerebral palsy Review for gene: AGAP1 was set to AMBER Added comment: Two individuals reported with de novo variants in this gene and a CP phenotype. Rare variants over-represented in a case-control study. Supportive zebrafish model. Another individual with a deletion (+1 other gene) reported with ID and autism. This seems the most appropriate panel? Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.239 | FAM50A |
Konstantinos Varvagiannis gene: FAM50A was added gene: FAM50A was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FAM50A 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: FAM50A were set to 32703943 Phenotypes for gene: FAM50A were set to Mental retardation syndrome, X-linked, Armfield type (MIM #300261) Penetrance for gene: FAM50A were set to unknown Review for gene: FAM50A was set to GREEN Added comment: Lee et al (2020 - PMID: 32703943) provide evidence that Armfield X-Linked intellectual disability syndrome is caused by monoallelic FAM50A pathogenic variants. The current review is based only on this reference. The authors provide clinical details on 6 affected individuals from 5 families. Features included postnatal growth delay, DD and ID (6/6 - also evident for those without formal IQ assesment), seizures (3/6 from 2 families), prominent forehead with presence of other facial features and variable head circumference (5th to >97th %le), ocular anomalies (5/6 - strabismus/nystagmus/Axenfeld-Rieger), cardiac (3/6 - ASD/Fallot) and genitourinary anomalies (3/6). In the first of these families (Armfield et al 1999 - PMID: 10398235), linkage analysis followed by additional studies (Sanger, NGS of 718 genes on chrX, X-exome NGS - several refs provided) allowed the identification of a FAM50A variant. Variants in other families were identified by singleton (1 fam) or trio-ES (3 fam). In affected individuals from 3 families, the variant had occurred de novo. Carrier females in the other families were unaffected (based on pedigrees and/or the original publication). XCI was rather biased in most obligate carrier females from the 1st family (although this ranged from 95:5 to 60:40). Missense variants were reported in all affected subjects incl. Trp206Gly, Asp255Gly, Asp255Asn (dn), Glu254Gly (dn), Arg273Trp (dn) (NM_004699.3). Previous studies have demonstrated that FAM50A has ubiquitous expression in human fetal and adult tissues (incl. brain in fetal ones). Immunostaining suggests a nuclear localization for the protein (NIH/3T3 cells). Comparison of protein levels in LCLs from affected males and controls did not demonstrate significant differences. Protein localization for 3 variants (transfection of COS-7 cells) was shown to be similar to wt. Complementation studies in zebrafish provided evidence that the identified variants confer partial loss of function (rescue of the morpholino phenotype with co-injection of wt but not mt mRNA). The zebrafish ko model seemed to recapitulate the abnormal development of cephalic structures and was indicative of diminished/defective neurogenesis. Transcriptional dysregulation was demonstrated in zebrafish (altered levels and mis-splicing). Upregulation of spliceosome effectors was demonstrated in ko zebrafish. Similarly, mRNA expression and splicing defects were demonstrated in LCLs from affected individuals. FAM50A pulldown followed by mass spectrometry in transfected HEK293T cells demonstrated enrichment of binding proteins involved in RNA processing and co-immunoprecipitation assays (transfected U-87 cells) suggested that FAM50A interacts with spliceosome U5 and C-complex proteins. Overall aberrant spliceosome C-complex function is suggested as the underlying pathogenetic mechanism. Several other neurodevelopmental syndromes are caused by variants in genes encoding C-complex affiliated proteins (incl. EFTUD2, EIF4A3, THOC2, etc.). Please consider inclusion in the ID panel with green rating and epilepsy panel with amber (seizures in individuals from 2 families). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.219 | NARS |
Konstantinos Varvagiannis changed review comment from: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model). As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy. Sources: Literature; to: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model). As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.219 | NARS |
Konstantinos Varvagiannis gene: NARS was added gene: NARS was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NARS were set to 32738225 Phenotypes for gene: NARS were set to Abnormal muscle tone; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Ataxia; Abnormality of the face; Demyelinating peripheral neuropathy Penetrance for gene: NARS were set to Complete Review for gene: NARS was set to GREEN Added comment: [Please note that HGNC Approved Gene Symbol for this gene is NARS1] Manole et al (2020 - PMID: 32738225) provide evidence that both biallelic and monoallelic (de novo) pathogenic NARS1 variants cause a neurodevelopmental disorder. In total 32 individuals from 21 families are reported, with biallelic variants identified in individuals from 13 families and de novo in 8 families. Similar features were reported for AR/AD occurrences of the disorder and included of microcephaly (90% - most often primary), epilepsy (23/32 or 74% - variable semiology incl. partial/myoclonic/generalized tonic-clonic seizures), DD and ID (as a universal feature), abnormal tone in several (hypotonia/spasticity), ataxia, demyelinating peripheral neuropathy (in 3 or more for each inheritance mode - or a total of 25%). Some individuals had dysmorphic features. NARS1 encodes an aminoacyl-tRNA synthetase (ARS) [asparaginyl-tRNA synthetase 1]. Aminoacyl-tRNA synthetases constitute a family of enzymes catalyzing attachment of amino-acids to their cognate tRNAs. As the authors comment, mutations in genes encoding several other ARSs result in neurological disorders ranging from peripheral neuropathy to severe multi-systemic NDD. Dominant, recessive or both modes for inheritance for mutations in the same gene (e.g. AARS1, YARS1, MARS1, etc) have been reported. Some variants were recurrent, e.g. the c.1600C>T / p.Arg534* which occurred in 6 families as a de novo event or c.1633C>T p.Arg545Cys (homozygous in 6 families). 3 different variants were reported to have occured de novo (c.965G>T - p.Arg322Leu, c.1525G>A - p.Gly509Ser, p.Arg534*) with several other variants identified in hmz/compound htz individuals. A single SNV (c.1067A>C - p.Asp356Ala) was suggested to be acting as modifier and pathogenic only when in trans with a severe variant. [NM_004539.4 used as RefSeq for all]. The authors provide several lines of evidence for a partial loss-of-function effect (e.g. reduction in mRNA expression, enzyme levels and activity in fibroblasts or iNPCs) underlying pathogenicity of the variants identified in individuals with biallelic variants. A gain-of-function (dominant-negative) effect is proposed for de novo variants (such effect also demonstrated for the p.Arg534* in a zebrafish model). As also Manole et al suggest, NARS1 can be considered for inclusion in gene panels for DD/ID, epilepsy and/or demyelinating neuropathy. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.201 | HIST1H4J |
Arina Puzriakova changed review comment from: This is a possible gene for intellectual disability with facial dysmorphism in G2P. Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length.; to: Added new-gene-name tag, new approved HGNC gene symbol is H4C11. This is a possible gene for intellectual disability with facial dysmorphism in G2P. Tessadori et al. (2020) (PMID: 31804630) reported a 14-year old Hispanic male with profound intellectual disability, who was heterozygous for a de novo (c.274 A>G, p.K91E) variant in HIST1H4J. Clinical features were said to resemble those reported in patients with HIST1H4C variants, which encodes an identical H4 protein to that of HIST1H4J. Functional data obtained in zebrafish showed the missense variant caused developmental defects, specifically resulting in defective head structures and reduced body axis length. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.176 | CCDC32 |
Eleanor Williams gene: CCDC32 was added gene: CCDC32 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CCDC32 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC32 were set to 32307552 Phenotypes for gene: CCDC32 were set to global developmental delay Review for gene: CCDC32 was set to AMBER Added comment: PMID: 32307552 - Harel et al 2020 - report 2 unrelated consanguineous families with probands with homozygous frameshift variants in CCDC32. Parents are heterozygous. Phenotype is a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies. In one family the child had global developmental delay, in the other the child had moderately delayed motor and language development and hyperactivity. Functional studies in zebrafish show that ccdc32 depletion impairs cilia formation and demonstrate a contribution of ccdc32 in craniofacial, brain and left/right axis development. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.153 | NOVA2 | Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.152 | NOVA2 | Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 terminating variants reported in unrelated cases, together supportive functional studies in a zebrafish knockdown of the NOVA2 ortholog (nova1a) (PMID 32197073). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.126 | EXOC7 |
Zornitza Stark gene: EXOC7 was added gene: EXOC7 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOC7 were set to 32103185 Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly Review for gene: EXOC7 was set to GREEN gene: EXOC7 was marked as current diagnostic Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration. We have added to the Microcephaly and Genetic Epilepsies panels as well. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.126 | PDCD6IP |
Zornitza Stark gene: PDCD6IP was added gene: PDCD6IP was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PDCD6IP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PDCD6IP were set to 32286682 Phenotypes for gene: PDCD6IP were set to microcephaly; Intellectual disability Review for gene: PDCD6IP was set to AMBER Added comment: One consanguineous family with 2 affected sibs with primary microcephaly (-4SD), intellectual disability and short stature (-5/6SD), and homozygous frameshift variant in PDCD6IP. The homozygous variant was confirmed in both affected sibs, while the four healthy siblings and parents were heterozygous. The clinical features observed in the patients were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.80 | HIST1H4J |
Zornitza Stark gene: HIST1H4J was added gene: HIST1H4J was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: HIST1H4J was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HIST1H4J were set to 31804630 Phenotypes for gene: HIST1H4J were set to microcephaly; intellectual disability; dysmorphic features Review for gene: HIST1H4J was set to AMBER Added comment: Single case report but with functional evidence in zebrafish and phenotypic similarity to HIST1H4C phenotype Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.35 | UGDH |
Konstantinos Varvagiannis gene: UGDH was added gene: UGDH was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UGDH were set to 32001716 Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792 Penetrance for gene: UGDH were set to Complete Review for gene: UGDH was set to GREEN Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants. The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever. Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode. UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM]. Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate). Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ. Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | RIC1 |
Zornitza Stark gene: RIC1 was added gene: RIC1 was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: RIC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RIC1 were set to 31932796 Phenotypes for gene: RIC1 were set to Cleft lip; cataract; tooth abnormality; intellectual disability; facial dysmorphism; ADHD Review for gene: RIC1 was set to AMBER Added comment: Zebrafish model and consanguineous families but homozygous-by-descent. One to watch. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.3 | NCAPG2 |
Zornitza Stark gene: NCAPG2 was added gene: NCAPG2 was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: NCAPG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NCAPG2 were set to 30609410 Phenotypes for gene: NCAPG2 were set to Khan-Khan-Katsanis syndrome, MIM# 618460 Review for gene: NCAPG2 was set to GREEN gene: NCAPG2 was marked as current diagnostic Added comment: Two unrelated families and an animal model (zebrafish). Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.0 | UGP2 |
Konstantinos Varvagiannis gene: UGP2 was added gene: UGP2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: UGP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UGP2 were set to 31820119 Phenotypes for gene: UGP2 were set to Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face Penetrance for gene: UGP2 were set to Complete Review for gene: UGP2 was set to GREEN Added comment: Perenthaler et al. (2019 - PMID: 31820119) provide evidence that homozygosity for a variant abolishing the start codon of the UGP2 transcript (NM_001001521.1) encoding the predominant (short) protein isoform in brain, leads to a severe epileptic encephalopathy. This variant (chr2:64083454A>G / NM_001001521.1:c.1A>G - p.?) is also predicted to result in a substitution of a methionine at position 12 by a valine of the longer UGP2 transcript (NM_006759.3:c.34A>G - p.Met12Val). The 2 isoforms differ only by 11 amino acids at the N-terminal and are otherwise expected to be functionally equivalent. The authors provide details on 22 individuals from 15 families (some of which consanguineous). Features included intractable seizures (in all), absence of developmental milestones (in all), progressive microcephaly, visual impairment. The authors reported also presence of somewhat similar facial features. Some of these individuals passed away early. Previous work-up in several of them (incl. SNP-array, gene panel testing and metabolic investigations) had not revealed any abnormality, apart from ROH in some individuals. In all cases, the homozygous UGP2 SNV was the only P/LP variant for the neurodevelopmental phenotype following exome/genome sequencing. Segregation studies in affected/unaffected family members were compatible. Families came from the Netherlands (but mostly from) India, Pakistan and Iran. Presence of a region of homozygosity shared between individuals from different families suggested that the variant might represent a mutation that originated several generations ago (in the area of Balochistan). The variant is present 15x in gnomAD, only in heterozygous state (in Asian mostly, reported once in Ashkenazi Jewish or Europeans) [ https://gnomad.broadinstitute.org/variant/2-64083454-A-G ]. UGP2 encodes UDP-glucose pyrophosphorylase which is an essential enzyme in sugar metabolism, catalyzing conversion of glucose-1-phosphate to UDP-glucose. UDP-glucose, in turn, serves as precursor for production of glycogen by glycogen synthase. The authors provide several lines of evidence for a the role of the gene in the CNS as well as for the deleterious effect of the specific variant : - In patient fibroblasts total UGP2 levels were not signifficantly different compared to parent / control fibroblasts, the longer isoform being upregulated (and stable) when the shorter is missing. Immunocytochemistry demonstrated similar localization of UGP2 in the case of mutant or wt cells. Enzymatic activity (/capacity to produce UDP-glucose) was similar between homozygous mut, heterozygous and wt fibroblasts. - In H9-derived neural stem cells, Western Blot, RT-PCR and qRT-PCR suggested that the short isoform is the predominant one. (In embryonic stem cells, or fibroblasts the ratio between short and long isoform was lower). - Analysis of RNA-seq data from human fetal tissues suggested that the short isoform is the predominant in brain. - UGP2 was detected upon immunohistochemistry in fetal brain tissues from first to third trimester of pregnancy while Western Blot confirmed preferential expression of the shorter isoform. - Homozygous embryonic (ESC) or neural stem cells (NSC) for the variant (knock-in/KI) or for a frameshift variant (knock-out/KO) were generated. Study of NSCs demonstrated reduced total UGP2 protein expression upon Western Blot in the case of KI cells and depleted in KO ones. Transcriptome analysis did not show major transcriptome alterations in KI/KO ESCs compared to wt. In NSC KI/KO cells transcriptome alterations were observed compared to wt with upregulation among others of genes for synaptic processes and genes implicated in epilepsy. - The absence of UGP2 was shown to result in reduced ability of KO/KI NSCs to produce UDP-glucose, reduced capacity to synthesize glycogen under hypoxia (rescued in the case of KO cells by overexpression of wt or long isoform), defects of protein glycosylation as well as in increased unfolded protein response (/susceptibility to ER stress). These alterations are commented to be possibly implicated in pathogenesis of epilepsy, progressive microcephaly, etc. - A CRISPR-Cas9 zebrafish model leading with loss of ugp2a and hypomorphic ugp2b (the zebrafish homologs of UGP2) demonstrated abnormal behavior, reduced eye movements and increased frequency/duration of movements upon stimulation with a potent convulsant (suggestive of increased seizure susceptibility). - UGP knockout in drosophila is lethal while flies compound heterozygous for hypomorphic alleles are viable but show a movement defects due to altered synaptogenesis secondary to glycosylation defects (cited PMID: 27466186). - The authors make speculations as for the occurrence of a single variant (and not others) eg. absence of UGP2 (in the case of LoF variants affecting both isoforms) would possibly be incompatible with life, Met12Val being tolerable for the long transcript not affecting stability/enzymatic activity (which may not be the case for other substitutions affecting Met12), etc. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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] |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1098 | AP1B1 |
Konstantinos Varvagiannis gene: AP1B1 was added gene: AP1B1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP1B1 were set to 31630788; 31630791 Phenotypes for gene: AP1B1 were set to Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability Penetrance for gene: AP1B1 were set to Complete Review for gene: AP1B1 was set to AMBER Added comment: Boyden et al. (2019 - PMID: 31630788) and Alsaif et al (2019 - PMID: 31630791) report on the phenotype related to biallelic AP1B1 mutations. Common features included failure to thrive, ichthyosis (with variable palmoplantar keratoderma/erythroderma/abnormal hair) and hearing loss. Each study focused on different additional features eg. thrombocytopenia or photophobia in all individuals reported by Boyden et al, while Alsaif et al. focused on abnormal copper metabolism (low plasma copper and ceruloplasmin) observed in all 3 affected individuals and enteropathy/hepatopathy observed in 2 sibs. DD was observed in all 3 individuals (2 families) reported by Alsaif et al. and patient 424 reported by Boyden et al. ID was noted in all individuals of relevant age (2 from 2 families) in the study by Alsaif. Boyden commented that ID is not part of the phenotype. The adult (424) - despite his early DD - was noted to have normal intellect and had graduated college. The other patient (1325) was last followed up at 11 months (still DD was not reported). AP1B1 encodes one of the large subunits (β1) of the adaptor protein complex 1. Each of the AP complexes is a heterotetramer composed of two large (one of γ, α, δ, ε and β1-β4 for AP-1 to AP-4 respectively), one medium (μ1-μ4) and one small (σ1-σ4) adaptin subunit. The complex is involved in vesicle-mediated transport. Variants were confirmed in probands and carrier parents (NM_001127.3): Boyden Pat424 (33y) : c.430T>C (p.Cys144Arg) in trans with c.2335delC (p.Leu779Serfs*26) Boyden Pat1325 (11m) [consanguineous Ashkenazi Jewish family] : homozygosity for c.2374G>T (p.Glu792*) Alsaif sibs P1,P2 (4y4m, 1y5m) [consanguineous - Pakistani origin] : homozygous for a chr22 75 kb deletion spanning only the promoter and ex1-2 of AP1B1 Alsaif P3 (4y6m) [consanguineous - Saudi origin] : homozygous for a c.38-1G>A Variant / additional studies : 22q 75-kb deletion: PCR deletion mapping and Sanger delineated the breakpoints of the 22q12.2 del to chr22:29758984-29815476 (hg?). Complete absence of transcript upon RT-PCR (mRNA from fibrolasts). Splicing variant (c.38-1G>A): RT-PCR confirmed replacement of the normal transcript by an aberrant harboring a 1 bp deletion (r.40del). Stopgain variant (c.2374G>T): Western blot demonstrated loss of AP1B1 (and marked reduction also for AP1G1) in cultured keratinocytes of the homozygous patient. Loss-of-function is the effect predicted by variants. Vesicular defects were observed in keratinocytes of an affected individual (homozygous for the nonsense variant). Rescue of these vesicular defects upon transduction with wt AP1B1 lentiviral construct confirmed the LoF effect. [Boyden et al.] ATP7A and ATP7B, two copper transporters, have been shown to depend on AP-1 for their trafficking. Similar to MEDNIK syndrome, caused by mutations in AP1S1 and having an overlapping phenotype with AP1B1 (also including hypocupremia and hypoceruloplasminemia), fibroblasts from 2 affected individuals (from different families) demonstrated abnormal ATP7A trafficking. [Alsaif et al.] Proteomic analysis of clathrin coated vesicles (2 ind from 2 fam) demonstrated that AP1B1 was the only AP1/AP2 CCV component consistently reduced in 2 individuals (from 2 families). [Alsaif et al.] Boyden et al. provided evidence for abnormal differentiation and proliferation in skin from an affected individual. In addition E-cadherin and β-catenin were shown to be mislocalized in keratinocytes from this affected individual. Loss of ap1b1 in zebrafish is not lethal but lead to auditory defects (/vestibular deficits). The inner ears appear to develop normally, although there is progressive degeneration of ear epithelia. There are no behavioral/neurological phenotypes listed for mouse models. [ http://www.informatics.jax.org/marker/MGI:1096368 ]. AP1B1 is not associated with any phenotype in OMIM/G2P/SysID. Overall this gene could be considered for inclusion in the ID panel probably with amber rating. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1091 | NKAP |
Catherine Snow Added comment: Comment on list classification: NKAP reviewed by Konstantinos Varvagiannis following publication by Fiordaliso et al. (PMID:31587868) who identified 10 males from 8 unrelated families with missense mutations in NKAP (on Xq24) Hypotonia and tall stature with Marfanoid habitus was predominant phenotype. One variant (NM_024528:c.988G>A / p.Arg333Gln) was seen in 4 families and although origin was not provided for all families this variant was seen in brothers with parents from Slovakia and an individual with parents from Japan. NKAP is not currently in OMIM or Gene2Phenotype. Rating NKAP as Green as consistent phenotype observed, >3 unrelated individuals and some functional work in Zebrafish. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1090 | METTL5 |
Rebecca Foulger Added comment: Comment on list classification: METTL5 was added to the panel and rated Green by Konstantinos Varvagiannis. There are just sufficient (3) cases from the literature (siblings in PMID:29302074 plus 2 families in PMID:31564433), and animal models (mice and zebrafish) exhibit microcephaly similar to the human phenotype. However, the Gly61Asp variant found in the PMID:29302074 siblings is currently classed as VUS and PMID:31564433 failed to demonstrate a functional impact for this variant on the encoded protein. METTL5 has been recently added (October 2019) to DD-G2P with a probable rating for 'Autosomal-Recessive Intellectual Disability and Microcephaly'. METTL5 is not yet associated with a disorder in OMIM. Given the uncertainty of the functional significance of the Gly61Asp variant, on balance an Amber rating is appropriate at this time, pending further cases or functional evidence. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1062 | CDH2 |
Konstantinos Varvagiannis changed review comment from: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants. Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2). CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells). Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc). Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified. One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy . Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible. Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects. Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel]. ------ The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID. ------ As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree). Sources: Literature; to: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants. Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2). CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells). Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc). Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified. One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy . Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible. Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects. Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel]. ------ The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID. ------ As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1062 | CDH2 |
Konstantinos Varvagiannis gene: CDH2 was added gene: CDH2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CDH2 were set to 31585109; 9015265; 17222817 Phenotypes for gene: CDH2 were set to Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability Penetrance for gene: CDH2 were set to unknown Review for gene: CDH2 was set to AMBER Added comment: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants. Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2). CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells). Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc). Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified. One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy . Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible. Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects. Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel]. ------ The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID. ------ As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1047 | METTL5 |
Konstantinos Varvagiannis gene: METTL5 was added gene: METTL5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: METTL5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: METTL5 were set to 29302074; http://doi.org/10.1016/j.ajhg.2019.09.007; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf Phenotypes for gene: METTL5 were set to Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality Penetrance for gene: METTL5 were set to Complete Review for gene: METTL5 was set to GREEN Added comment: [1] - PMID: 29302074 : In a WES/WGS study of 404 consanguineous families with two or more offspring affected by ID, Hu et al. identified two sibs homozygous for a METTL5 missense variant [NM_014168:c.182G>A / p.Gly61Asp]. These 2 subjects, born to first cousin parents from Iran, presented with early learning impairment, aggressive behaviour, severe microcephaly (-7SD and -8SD) and ID formally evaluated to be in the severe range. Sanger confirmation of variants and segregation studies were performed for all available and informative members in families participating in the study. In silico predictions were all in favour of a deleterious effect (PolyPhen2, MutationTaster, SIFT, CADD) and the variant was absent from ExAC. The effect of the specific variant was studied in ref. 2 (below). [2] - DOI: 10.1016/j.ajhg.2019.09.007 : Richard et al. (2019) reported on 5 additional individuals from 2 consanguineous families. Common phenotype consisted of speech delay, moderate/severe ID (4/4), microcephaly (4/4 - though milder than in the first report), behavioral problems (ADHD, aggressiveness, autistic feat.) and possibly some overlapping facial features (nose and ear abnormalities). 3 sibs from the 1st family, from Pakistan, were homozygous for a frameshift variant (NM_014167.2:c.344_345delGA / p.Arg115Asnfs*19) while sibs from the 2nd family, from Yemen, were homozygous for p.Lys191Valfs*1 (c.571_572delAA). Confirmation and segregation studies supported a role for the variants. The authors performed additional studies for METTL5 and all 3 variants reported to date, notably: - Based on RNA-seq data from the Allen Brain Atlas, METTL5 is expressed in the developing and adult human brain (incl. cerebellar cortex, hippocampus and striatum). - Immunostaining in mouse brain demonstrated ubiquitous expression (postnatal day 30). - In rat hippocampal neurons, enrichment of METTL5 was found in the soma, the nucleus and pre- and post- synaptic regions. - Myc-/GFP-tagged METTL5 wt or mutants were transiently expressed in COS7 cells, and were found in the cytoplasm and nucleus. Levels of the 2 frameshift variants were significantly reduced compared with wt, although this was not the case for Gly61Asp. - Upon transfection of rat hippocampal neurons, METTL5-GFP tagged wt and mt proteins showed similar localicalization in nucleus and dendrites. - Western blot on HEK293T cells transfected with Myc-METTL5 wt or mt constructs demonstrated decreased amounts for the frameshift (but not the missense) variants while comparison after addition of a proteasome inhibitor or cyclohexamide suggested that this is not probably due to decreased mutant protein - rather than mRNA (NMD) - stability. - In zebrafish, morpholino knockdown of mettl5 led to reduced head size and head/body ratio (reproducing the microcephaly phenotype) and curved tails. Forebrain and midbrain sizes were also significantly reduced. Based on the ACMG criteria, Gly61Asp is classified as VUS (PM2, PP1, PP3) and the frameshift ones as pathogenic (PS3, PM2, PM4, PP1, PP3). The authors comment that METTL5 is an uncharacterized member of the methyltransferase superfamily (of 33 METTL proteins). Variants in other methyltransferase-like genes (mainly METTL23) have been associated with ID, while various histone-/DNA-/tRNA-/rRNA- methyltransferases such as EHMT1, DNMT3A, NSUN2, FTSJ1, etc have been implicated in ID. Given the role of methyltransferases in neurodevelopment and neuroplasticity, homology comparisons suggesting presence of relevant domain in METTL5 and accumulation of the protein in the nucleus, a role as epigenetic regulator is proposed (see also ref. 3). [3] - Conference abstract by Helmut et al. ["A novel m6A RNA methyltransferase in mammals - characterization of Mettl5 mutant mice in the German Mouse Clinic" - Oral presentation in the 33rd International Mammalian Genome Conference Sept. 2019 - available at : https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf ] The group using an in vitro methyltransferase assay, identified METTL5 as a m6A RNA methyltransferase. Generation of Mettl5-knockout mice using the CRISPR/Cas technology, suggested that homozygous mice are subviable, with lower body mass and abnormal growth of nasal bones in half. Homozygous mice were hypoactive and hypoexploratory during an open field test at the age of 8 weeks, while further alterations were observed in neurological functions. Phenotypic deviations were absent or very mild in heterozygous animals. As a result, the mouse model appeared to recapitulate relevant human phenotypes (microcephaly, ID and growth retardation). ---- There is no associated entry in OMIM (neither for the gene nor for a related disorder). G2P does not list any phenotype for this gene, either. METTL5 is included in the SysID database as a current primary ID gene (cited: 27457812, 28097321 / Given the shared co-authors with the study by Richard et al. as well as the overlapping variants, these articles probably report on the same individuals recently described in more detail). The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). ---- Overall, METTL5 could be considered for inclusion in the ID panel probably as green (3 families, 3 variants, segregation, suggested role of the gene, relevant expression patterns, some evidence at the variant-level, zebrafish and mouse models) or amber (underlying effect of Gly61Asp unknown and variant classified as VUS). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1021 | KATNB1 |
Konstantinos Varvagiannis gene: KATNB1 was added gene: KATNB1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: KATNB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KATNB1 were set to 25521378; 25521379; 26640080 Phenotypes for gene: KATNB1 were set to Lissencephaly 6, with microcephaly (MIM 616212) Penetrance for gene: KATNB1 were set to Complete Review for gene: KATNB1 was set to GREEN gene: KATNB1 was marked as current diagnostic Added comment: Biallelic pathogenic KATNB1 variants cause Lissencephaly 6, with microcephaly (MIM 616212). At least 13 affected individuals from 9 (mostly consanguineous) families have probably been reported in the following articles: - Mishra-Gorur et al. (2014 - PMID: 25521378) [7 individuals from 5 unrelated families] - Hu et al. (2014 - PMID: 25521379) [5 individuals from 3 families] - Yigit el al. (2016 - PMID: 26640080) [1 subject born to consanguineous parents] The phenotype appears to be relevant to the current panel. Several different variants have been reported to date. Extensive studies as for the impact of mutations at the cellular level as well as animal models (zebrafish, mouse, drosophila) support involvement of KATNB1. These arguments, provided mainly by the first two studies, are summarized in the respective OMIM entry for the disorder : https://omim.org/entry/616212 (variants and their effect are discussed in the entry for KATNB1 - https://omim.org/entry/602703). The individual reported by Yigit el al. was a 5 year-old girl with - among others - severely delayed psychomotor development. The child was found to harbor a homozygous splice site variant (removing the acceptor AG signature). Confirmation of the variant and segregation studies were performed with Sanger sequencing. cDNA studies were carried out and demonstrated aberrant splicing. KATNB1 is not associated with any disorder in G2P. The gene is included in panels for ID offered by several diagnostic laboratories (incl. Radboudumc). As a result, this gene can be considered for inclusion in the current panel probably as green (or amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1015 | FBXW11 |
Konstantinos Varvagiannis gene: FBXW11 was added gene: FBXW11 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FBXW11 were set to 31402090 Phenotypes for gene: FBXW11 were set to Global developmental delay; Intellectual disability; Abnormality of the eye; Abnormality of the head; Abnormality of digit Penetrance for gene: FBXW11 were set to unknown Review for gene: FBXW11 was set to GREEN Added comment: Holt et al. (2019 - PMID: 31402090) report on 7 unrelated individuals with de novo FBXW11 variants. Features included DD (6/7), ID (6/7 - severity relevant to the current panel in most cases), eye, digital, jaw anomalies, etc. There was some overlap with the phenotype of a 1.24-Mb 5q35.1 microduplication spanning FBXW11 and 6 additional genes (Koolen et al, 2006 - PMID: 16865294). FBXW11 encodes an F-box protein part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degratation. The SCF complex functions as a regulator of Wnt/β-catenin, Hh (and possibly RAS) signalling pathways. Each individual harbored a private missense variant as a de novo event. Alternative diagnoses (eg. Noonan syndrome in the case of a suggestive phenotype) were ruled out to the extent possible. All 7 variants localized in regions depleted for nonsynonymous variation (constrained coding regions) at the tips of loops of the WD repeat domains and were presumed to lead to destabilization of the protein and/or its interactions. Given the clustering a gain-of-function or dominant-negative effect of these variants might be suggested. [In gnomAD FBXW11 has a Z score = 3.96 for missense variants / pLI = 0.98]. In situ hybridization on human embryo sections demonstrated expression in the developping eye, hand, brain and mandibular process. Relevant expression patterns were also observed for the 2 zebrafish orthologs of FBXW11, fbxw11a/b. Generated zebrafish homozygous for a frameshift fbxw11b frameshift variant demonstrated relevant phenotypes upon additional injection of a fbxw11a morpholino (abnormal pectoral fins, heart edema, smaller eyes, abnormal jaw development). FBXW11 is not associated with any phenotype in OMIM/G2P. As a result, this gene can be considered for inclusion in the ID panel as green (sufficient cases, expression, phenotype in zebrafish model, etc.) or amber. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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] |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.996 | WDR37 |
Konstantinos Varvagiannis gene: WDR37 was added gene: WDR37 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WDR37 were set to 31327510; 31327508 Phenotypes for gene: WDR37 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of the eye; Abnormality of nervous system morphology; Hearing abnormality; Abnormality of the cardiovascular system; Abnormality of the skeletal system; Abnormality of the genitourinary system Penetrance for gene: WDR37 were set to unknown Review for gene: WDR37 was set to GREEN Added comment: Two concurrent publications by Reis et al. and Kanca et al. (2019 - PMIDs: 31327510, 31327508) report on the phenotype of individuals with de novo WDR37 mutations. The study by Reis et al. provides clinical details on 4 affected individuals, while 5 further are described by Kanca et al. 4 different de novo variants were reported in these individuals who appear to be unrelated in (and between) the 2 studies [NM_014023.3]: - c.356C>T (p.Ser119Phe) [Reis indiv. 1 - 3y, Kanca proband 3 - 5m2w] - c.389C>T (p.Thr130Ile) [Reis indiv. 2 - 22m , Kanca proband 5 - 6w] - c.374C>T (p.Thr125Ile) [Reis indiv. 3 - 8y , Kanca proband 1 - 7y] - c.386C>G (p.Ser129Cys) [Reis indiv. 4 - unkn age, Kanca probands 2 and 4, 6.5y and 19y] Common features included DD/ID (severity relevant for the current panel), seizures (9/9), ocular anomalies (corneal opacity/Peters anomaly, coloboma, microphthalmia etc.) and variable brain, hearing, cardiovascular, skeletal and genitourinary anomalies. Some facial and/or other dysmorphic features (incl. excess nuchal skin / webbed neck) were also frequent among affected individuals. Feeding difficulties and growth deficiency were also among the features observed. The function of WDR37 is not known. Variants demonstrated comparable protein levels and cellular localization compared to wt. Reis et al. provide evidence using CRISPR-Cas9 mediated genome editing in zebrafish, to introduce the Ser129Cys variant observed in affected individuals as well as novel missense and frameshift variants. Poor growth (similar to the human phenotype) and larval lethality were noted for missense variants. Head size was proportionately small. Ocular (coloboma/corneal) or craniofacial anomalies were not observed. Zebrafish heterozygous for LoF variants survived to adulthood. Based on these a dominant-negative mechanism was postulated for missense alleles. RNA-seq analysis in zebrafish showed upregulation of cholesterol biosynthesis pathways (among the most dysregulated ones). Previous data in mice, suggest a broad expression pattern for Wdr37 with enrichment in ocular and brain tissues, significant associations in homozygous mutant mice for decreased body weight, grip strength, skeletal anomalies and possible increase (p =< 0.05) in ocular (lens/corneal) and other anomalies [BioGPS and International Mouse Phenotyping Consortium cited]. CG12333 loss (the Drosophila WDR37 ortholog) causes increased bang sensitivity in flies (analogous to the human epilepsy phenotype), defects in copulation and grip strength, phenotypes that were rescued by human reference but not variant cDNAs. As discussed by Kanca et al. based on data from Drosophila and mice, limited phenotypic similarity of CNVs spanning WDR37 and adjacent genes with the reported individuals and the presence of LoF variants in control populations haploinsufficiency appears unlikely. Gain-of-function is also unlikely, as expression of human variants in flies did not exacerbate the observed phenotypes. A dominant-negative effect is again proposed. WDR37 is not associated with any phenotype in OMIM/G2P. As a result WDR37 can be considered for inclusion in the ID and epilepsy panels with green (relevant phenotype, sufficient cases, animal models) or amber rating. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.847 | DYNC1I2 |
Konstantinos Varvagiannis gene: DYNC1I2 was added gene: DYNC1I2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DYNC1I2 were set to 31079899 Phenotypes for gene: DYNC1I2 were set to Microcephaly; Intellectual disability; Abnormality of nervous system morphology; Abnormality of head or neck Penetrance for gene: DYNC1I2 were set to Complete Review for gene: DYNC1I2 was set to AMBER Added comment: Ansar et al. (2019 - PMID: 31079899) report on five individuals from 3 families, with biallelic likely pathogenic DYNC1I2 variants. The phenotype consisted of microcephaly, intellectual disability, cerebral malformations and suggestive facial features. 2/5 individuals, from different families presented seizures. Affected individuals from a consanguineous Pakistani family were homozygous for a splicing variant (c.607+1G>A - RNA was unavailable for further studies). One individual from a futher family was compound heterozygous for a missense variant (c.740A>G or p.Tyr247Cys) and a 374 kb deletion encompassing DYNC1I2 as well as 3 other genes (DCAF17, CYBRD1, SLC25A12). Another individual was found to harbor c.740A>G (p.Tyr247Cys) in trans with c.868C>T (p.Gln290*). [NM_001378.2 used as reference]. DYNC1I2 encodes Dynein Cytoplasmic 1 intermediate chain 2, a component of the cytoplasmic dynein 1 complex. This complex is involved in retrograde cargo transport within the cytoplasmic microtubule network. Emerging evidence suggests a critical role of this complex in neurodevelopment and homeostasis (PMIDs cited by the authors: 25374356, 28395088). Mutations in other genes encoding components of the complex (principally DYNC1H1) give rise to neurological disorders, some of which with ID as a principal feature (eg. Mental retardation, autosomal dominant 13 - MIM 614563). In zebrafish, DYNC1I2 has 2 orthologs - dync1i2a and dync1i2b. The former is suggested to be the functionally relevant DYNC1I2 ortholog as CRISPR-Cas9 dync1i2a disruption and/or suppression with morpholinos resulted in altered craniofacial patterning and reduction in head size (similar to the microcephaly phenotype reported in affected individuals). In vivo complementation studies suggested a loss of function effect for the p.Tyr247Cys variant, similar to the p.Gln290* one. Evidence is provided for a role of increased apoptosis, probably secondary to altered cell cycle progression (prolonged mitosis due to abnormal spindle morphology), to explain the reduced head size/microcephaly phenotype. There is no associated phenotype in OMIM/G2P. As a result, DYNC1I2 could be considered for inclusion in the ID panel probably as amber (ID reported for 5 individuals from 3 families, severity of ID not specified for all, eg. fam. 2 for whom the deletion was also spanning other genes which might contribute to the phenotype). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.588 | CWF19L1 |
Konstantinos Varvagiannis gene: CWF19L1 was added gene: CWF19L1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: CWF19L1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CWF19L1 were set to 25361784 Phenotypes for gene: CWF19L1 were set to Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127) Penetrance for gene: CWF19L1 were set to Complete Review for gene: CWF19L1 was set to GREEN gene: CWF19L1 was marked as current diagnostic Added comment: Biallelic pathogenic variants in CWF19L1 cause Spinocerebellar ataxia, autosomal recessive 17 (MIM 616127). ------- Burns et al. (2014 - PMID: 25361784) report on 2 sibs born to consanguineous parents, homozygous for a splice site variant (NM_018294.5:c.964+1G>A). Congenital ataxia with hypoplasia of vermis and cerebellar hemispheres and ID were features reported in both in this study. Clinical details on this family were published previously (Yapici and Eraksoy - PMID: 15981765) where ID appeared to be a feature for one of the sibs (FSIQ of 68) but not the other (IQ of 90) [the sibs seem to correspond to patients 5 and 6 from the third family of the original report]. Expression in patient lymphoblastoid cell lines was reduced using expression micro-arrays and quantitative reverse-transcription PCR. The variant was shown to lead to skipping of exon 9. Introduction of an out-of-frame stop codon (thus NMD) may explain mRNA levels. Western blot using epitope spanning exons 5-7 demonstrated absence (in patient but not in control LCLs) of the 2 protein bands expected based on this epitope. [A shorter isoform due to downstream alternative start site would not be detectable]. Using commercial normal tissue brain lysates revealed only the canonical protein band suggesting that this is the isoform present in brain. Morpholino knockdown of cwf91l1 in zebrafish resulted in altered cerebellar staining (/structure) and abnormal motor behavior. -------- Nguyen et al. (2016 - PMID: 26197978) report on a further individual with ID, ataxia and abnormal cerebellum (extensive discussions whether this represents hypoplasia/atrophy) compound heterozygous for a missense (NM_018294.4:c.37G>C / p.Asp13His) and a nonsense variant (c.946A>T / p.Lys316*). mRNA expression in patient fibroblasts was similar to control while cDNA sequence analysis was suggestive of lower levels for the r.946A>U transcript (compared to r.37G>C) possibly due to NMD. -------- Evers et al. (2016 - PMID: 27016154) report on a further individual, born to consanguineous parents, homozygous a frameshift variant (NM_018294.5:c.467delC or p.Pro156Hisfs). This individual presented with ID, ataxia and similar cerebellar anomalies. cDNA of 3 different regions of CWF19L1 suggested tht mRNA was not entirely degraded by NMD. Western blot demonstrated absence of a band corresponding to the longest isoform in patient LCL cells. [All isoforms discussed in Fig3]. A subsequent pregnancy of the same couple was terminated due to presence of additional fetal anomalies possibly not explained by homozygosity (only) for this variant which was confirmed (cerebellar measurements were in the the low-normal range and morphology reportedly normal). -------- In ClinVar additional variants have been submitted as pathogenic/likely pathogenic (although a phenotype is not specified for all). -------- CWF19L1 is not associated with any phenotype in G2P. This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). -------- As a result CWF19L1 can be considered for inclusion in this panel probably as green (rather than amber). Sources: Literature, Radboud University Medical Center, Nijmegen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.584 | ZBTB11 |
Konstantinos Varvagiannis gene: ZBTB11 was added gene: ZBTB11 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: ZBTB11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZBTB11 were set to 29893856; 28382966 Phenotypes for gene: ZBTB11 were set to Intellectual disability Penetrance for gene: ZBTB11 were set to Complete Review for gene: ZBTB11 was set to AMBER Added comment: Fattahi et al. (PMID: 29893856) report on 9 individuals from 2 broader consanguineous pedigrees with biallelic ZBTB11 mutations. Features in the first family (from Iran) consisted of moderate ID, microcephaly, ataxic gait, and spasticity with MRI findings of cerebellar atrophy and ventriculomegaly. Individuals from the second family (from Pakistan) presented with moderate ID and variable features. Homozygosity for missense ZBTB11 variants, private to each family was shown (NM_014415.3:c.2185C>T / p.H729Y and c.2640T>G / p.H880Q for the first and second family respectively). As the authors note, ZBTB11 is predicted to be a zinc finger transcriptional regulator and one of the hypotheses emitted suggests possible disruption of DNA binding. Functional studies performed demonstrated that the mutant proteins were excluded from the nucleolus where the (wt) protein localizes. Previous zebrafish models (PMID: 28382966) suggested CNS degeneration among other phenotypes in Zbtb11 mutants. Knockdown of the drosophila ZBTB11-ortholog (CkIIα-i1) resulted in recognizable shrinking of the mushroom body with significant reduction in the number of neurons compared to controls. Other Zinc Finger and BTB Domain-Containing proteins cause disorders with ID as a prominent feature (eg. ZBTB16, ZBTB20, etc.). ZBTB11 is not associated with any phenotype in OMIM nor in G2P. As a result, this gene can be considered for inclusion in this panel probably as amber (2 pedigrees only) or green (given the supportive functional studies). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.537 | GNB5 |
Konstantinos Varvagiannis gene: GNB5 was added gene: GNB5 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: GNB5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNB5 were set to 27523599; 27677260; 28697420; 29368331 Phenotypes for gene: GNB5 were set to Intellectual developmental disorder with cardiac arrhythmia, 617173; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmia, 617182 Penetrance for gene: GNB5 were set to Complete Review for gene: GNB5 was set to GREEN gene: GNB5 was marked as current diagnostic Added comment: Biallelic GNB5 pathogenic variants cause Intellectual developmental disorder with cardiac arrhythmia (MIM 617173) or language delay and ADHD/cognitive impairment with or without cardiac arrhythmia (MIM 617182). PMID: 27523599 is the first report on the associated phenotype. A total of 9 individuals from 6 different families (from various ethnic backgrounds) are described. The common features included hypotonia (noted in 6 out of 9 patients), intellectual disability (9/9 - in 3 cases mild, in 6 severe), heart rate disturbance (9/9 - in most cases sick sinus syndrome), seizures (4/9), ophthalmological problems (nystagmus in 6 out of 7 for whom this information was available) as well as gastric problems (5/8 with G-E reflux). The 6 variants (summarized in table S1) included : 2 nonsense mutations, 1 synonymous (demonstrated to affect splicing and leading to retention of 25 intronic bp), 2 further splice variants (positions +1 and +3) and a missense one (S81L). Nonsense mediated decay was the case for the product of the synonymous/splice variant as well as for a stopgain one. As noted by the authors, individuals homozygous for the S81L variant had a less severe phenotype - among others - with mild degree of intellectual disability. Functional studies included knockout of gnb5 in zebrafish, which was able to reproduce the human neurological, cardiac and ophthalmological phenotypes. Alternative causes for these phenotypes (incl. chromosomal or metabolic disorders) were ruled out. Affected individuals might benefit interventions for their heart rate disturbance as appears to be the case in the article as well as subsequent studies. PMID: 27677260 describes an extended consanguineous Saudi family with 5 individuals homozygous for the S81L variant. Common features included severe language delay, ADHD, but normal cognition in those available for evaluation. Seizures were not reported. Pathogenicity of the S81L variant is further supported by functional studies. PMID: 28697420 describes in detail 2 individuals from a large consanguineous pedigree confirmed to be homozygous for a single nucleotide deletion in GNB5. The phenotype included severe DD/ID, seizures, sinus bradycardia with frequent sinus pauses and ophthalmological problems. Sinus arrhythmia and or seizures were documented in several other relatives deceased and unavailable for testing. PMID: 28327206 reports on 2 subjects previously included in PMID: 27523599. PMID: 29368331 describes a child with severe developmental delay, nystagmus and sinus arrhythmia necessitating a pacemaker. EEG was abnormal although no frank seizures were observed. The child was compound heterozygous for a novel missense variant (R246Q) as well a 5 basepair deletion. GNB5 is included in diagnostic gene panels for intellectual disability offered by different laboratories. As a result this gene can be considered for inclusion in this panel as green. Sources: Literature, Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.468 | BRAF | Louise Daugherty Source Victorian Clinical Genetics Services was added to BRAF. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | BRAF | BRIDGE consortium edited their review of BRAF | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | BRAF | BRIDGE consortium edited their review of BRAF | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | BRAF | BRIDGE consortium reviewed BRAF | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||