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| Intellectual disability - microarray and sequencing v5.251 | CLCNKB |
Sarah Leigh Tag digenic was removed from gene: CLCNKB. Tag monogenic-polygenic tag was added to gene: CLCNKB. |
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| Intellectual disability - microarray and sequencing v3.1711 | DOCK8 | Sarah Leigh Phenotypes for gene: DOCK8 were changed from Mental retardation, autosomal dominant 2, 614113Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700; HYPERIMMUNOGLOBULIN E RECURRENT INFECTION SYNDROME AUTOSOMAL RECESSIVE (AR-HIES) to Intellectual developmental disorder, autosomal dominant 2, OMIM:614113 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v3.1540 | SLC5A6 | Arina Puzriakova Phenotypes for gene: SLC5A6 were changed from Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis to Neurodegeneration, infantile-onset, biotin-responsive, OMIM:618973 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| Intellectual disability - microarray and sequencing v3.1069 | PTPN4 |
Zornitza Stark gene: PTPN4 was added gene: PTPN4 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PTPN4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PTPN4 were set to 17953619; 25424712; 30238967; DOI: https://doi.org/10.1016/j.xhgg.2021.100033 Phenotypes for gene: PTPN4 were set to Intellectual disability Review for gene: PTPN4 was set to GREEN gene: PTPN4 was marked as current diagnostic Added comment: >3 unrelated probands and supportive mouse model PMID: 17953619 - knockout mouse model has impaired motor learning and cerebellar synaptic plasticity PMID: 25424712 - twins with a de novo whole gene deletion and a Rett-like neurodevelopmental disorder PMID: 30238967 - mosaic de novo variant (p.Leu72Ser) identified in a child with developmental delay, autistic features, hypotonia, increased immunoglobulin E and dental problems. Also supporting mouse assays demonstrating loss of protein expression in dendritic spines DOI: https://doi.org/10.1016/j.xhgg.2021.100033 - missense and truncating variants in six unrelated individuals with varying degrees of intellectual disability or developmental delay. 5 were able to undergo segregation analysis and found to be de novo. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.421 | NOG |
Arina Puzriakova Source Expert Review Red was added to NOG. Rating Changed from Amber List (moderate evidence) to Red List (low evidence) |
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| Intellectual disability - microarray and sequencing v3.314 | LMNB1 |
Konstantinos Varvagiannis gene: LMNB1 was added gene: LMNB1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: LMNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LMNB1 were set to 32910914 Phenotypes for gene: LMNB1 were set to Global developmental delay; Intellectual disability; Microcephaly; Short stature; Seizures; Abnormality of the corpus callosum; Cortical gyral simplification; Feeding difficulties; Scoliosis Penetrance for gene: LMNB1 were set to unknown Mode of pathogenicity for gene: LMNB1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: LMNB1 was set to GREEN Added comment: Cristofoli et al (2020 - PMID: 32910914) report 7 individuals (from 5 families) harboring mostly de novo LMNB1 variants. The common phenotype consisted of primary microcephaly (7/7 ranging from -4.4 to -10 SD), DD/ID (7/7), relative short stature in most (+0.7 to -4 SD). Additional features included brain MRI abnormalities (abnormal CC in 3, simplified gyral pattern in 3, small structurally normal brain, etc), seizures (4 individuals from 2 families), limb spasticity (1/7), cortical visual impairment (in 3), feeding difficulties (5/7), scoliosis (4/7). Non-overlapping dysmorphic features were reported in some. Variants were identified by WES or custom-designed gene panel and included 3 missense variants, 1 in-frame deletion and a splice variant. The in-frame deletion was inherited from a similarly affected parent in whom the variant occurred as a dn event. The splice SNV(NM_005573.3:c.939+1G>A) occurred in 3 sibs and was present as mosaic variant (15%) in the parent. This variant was predicted to result to extension of exon 5 by 6 amino-acids (samples were unavailable for mRNA studies). LMNB1 encodes a B-type lamin (the other being encoded by LMNB2). A- and B- type lamins are major components of the nuclear lamina. As the authors comment, LMNB1 is expressed in almost all cell types beginning at the earliest stages of development. Lamin-deficient mouse models support an essential role of B-type lamins in organogenesis, neuronal migration, patterning during brain development. Functional studies performed, demonstrated impaired formation of LMNB1 nuclear lamina in LMNB1-null HeLa cells transfected with cDNAs for 3 missense variants. Two variants (Lys33Glu/Arg42Trp) were shown to result in decreased nuclear localization with increased abundance in the cytosolic fraction. In patient derived LCLs these variants led to abnormal nuclear morphology. A missense variant in another domain (Ala152Gly - 1st coil domain) resulted also in lower abundance of lamin B1, irregular lamin A/C nuclear lamina, as well as more condensed nuclei (HeLa cells). LMNB1 duplications or missense mutations increasing LMNB1 expression are associated with a different presentation of AD leuodystrophy. A variant previously associated with leukodystrophy (Arg29Trp) was shown to behave differently (present in the nuclear extract but not in the cytosol, lamin B1 to A/C ratio in nuclear extract was not significantly altered compared to wt as was the case for Arg42Trp, Lys33Glu). Given the pLI score of 0.55 as well as the phenotype of individuals with deletions (not presenting microcephaly) the authors predict that a dominant-negative effect applies (rather than haploinsufficiency). Consider inclusion in the following panels : DD/ID (green), epilepsy (amber - 4 of 7 patients belonging to 2 families), primary microcephaly (green), callosome (amber/green - 3 individuals belonging to 3 families), mendeliome (green), etc. Sources: Literature |
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| Intellectual disability - microarray and sequencing v3.253 | NOG | Arina Puzriakova commented on gene: NOG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
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| Intellectual disability - microarray and sequencing v3.3 | NOG | Zornitza Stark reviewed gene: NOG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Brachydactyly, type B2, MIM# 611377, Multiple synostoses syndrome 1, MIM# 186500, Stapes ankylosis with broad thumbs and toes, MIM# 184460, Symphalangism, proximal, 1A, MIM# 185800, Tarsal-carpal coalition syndrome, MIM# 186570; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing v2.1135 | SLC5A6 |
Konstantinos Varvagiannis changed review comment from: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature; to: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1135 | SLC5A6 |
Konstantinos Varvagiannis gene: SLC5A6 was added gene: SLC5A6 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC5A6 were set to 27904971; 31392107; 31754459; 23104561; 29669219 Phenotypes for gene: SLC5A6 were set to Feeding difficulties; Failure to thrive; Global developmental delay; Developmental regression; Intellectual disability; Seizures; Microcephaly; Cerebral atrophy; Abnormality of the corpus callosum; Vomiting; Chronic diarrhea; Gastrointestinal hemorrhage; Abnormal immunoglobulin level; Osteopenia; Abnormality of metabolism/homeostasis Penetrance for gene: SLC5A6 were set to Complete Review for gene: SLC5A6 was set to GREEN Added comment: SLC5A6 encodes the sodium dependent multivitamin transporter (SMVT), a transporter of biotin, pantothenate and lipoate. The transporter has a major role in vitamin uptake in the digestive system (among others is the sole transporter for intestinal uptake of biotin which is not synthesized and but must be obtained from exogenous sources) as well as transport across the blood-brain barrier (SMVT being responsible for 89% of biotin transport) [several refs provided by Subramanian et al and Byrne et al]. 4 affected individuals from 3 families have been reported. Subramanian et al (2017 - PMID: 27904971) et al reported on a girl with feeding difficulties and failure to thrive (requiring nasogastric tube placement), microcephaly, DD (at 15m developmental age corresponding to 6m with features suggestive of spastic cerebral palsy), occurrence of multiple infections, osteoporosis and pathologic bone fractures. MRIs suggested brain atrophy, thin CC and hypoplasia of the pons. Metabolic (AA, OA) investigations and array-CGH were normal. Whole exome sequencing revealed presence of a missense (Arg123Leu - RefSeq not provided) and a nonsense (Arg94Ter) SLC5A6 variant. Serum biotin was normal although - at the time - the child was on parenteral and G-T nutrition. Following administration of biotin, pantothenic acid and lipoic acid the child demonstrated among others improved motor and verbal skills, head growth and normalization of immunoglobulin levels. Transfection of mutants in human derived intestinal HuTu-80 cells and brain U87 cells was carried out and a 3H-biotin assay showed no induction in biotin uptake confirming impaired functionality of the transporter. While wt protein displayed normal expression/membrane localization, Arg94Ter was poorly expressed with ectopic localization (cytoplasm). Arg123Leu was retained predominantly intracellularly, probably in the ER as was further supported by colocalization with DsRed-ER. Evidence from the literature is provided that deficiencies of the specific vitamins explain the clinical features (DD, microcephaly, immunological defect, osteopenia, etc). Schwantje et al (2019 - PMID: 31392107) described a girl with severe feeding problems, vomiting with blood (suspected Mallory-Weiss syndrome), poor weight gain and delayed gross motor development. The child presented an episode of gastroenteritis associated with reduced consciousness, circulatory insufficiency and metabolic derangement (hypoglycemia, severe metabolic acidosis, hyperammonemia, mild lactate elevation, ketonuria). Investigations some months prior to the admission (?) were suggestive of a metabolic disorder due to elevated plasma C3-carnitine, C5-OH-carnitine and elevated urinary excretion of 3-OH-isovaleric acid (biotinidase deficiency was considered in the DD but enzymatic activity was only marginally decreased). Biotin supplementation was initiated. Trio-exome sequencing (at 3yrs) demonstrated compound heterozygosity for 2 frameshift variants [NM_021095.2:c.422_423del / p.(Val141Alafs*34) and c.1865_1866del]. Following this result, increase of biotin supplementation and introduction of pantothenic acid, GI symptoms (incl. chronic diarrhea) resolved and the child displayed improved appetite and growth, yet a stable motor delay. The authors cite previous studies of conditional ko mice, displaying intestinal mucosal abnormalities and growth defects (similar to the child's problems), prevented by biotin and pantothenic acid supplementation. Byrne et al (2019 - PMID: 31754459) reported on a sibling pair with severe motor/speech developmental regression following a plateau (at 12m and 14m), development of ataxia and dyskinetic movements (both), seizures (one). Feeding difficulties, reflux and failure to thrive required N-G/gastrostomy feeding while both presented GI hemorrhage (in the case of the older sib, lethal). Other features in the youngest sib included brain MRI abnormalities (cerebral/cerebellar atrophy, thin CC, etc) and IgG deficiency. Biochemical, single-gene testing and mtDNA sequencing were not diagnostic. Exome in one, revealed presence of a frameshift [c.422_423del as above] and a missense variant (Arg400Thr). Sanger sequencing confirmed variants in both sibs and heterozygosity in parents. HeLa cells transfected with empty vector, wt or mut expression constructs confirmed significantly decreased 3H-biotin uptake for mut constructs compared to wt (and similar to empty vector). Parenteral triple vitamin replacement at the age of ~7 years resulted in improved overall condition, regain of some milestones, attenuation of vomiting, and resolution of peripheral neuropathy. Seizure were well-controlled (as was the case before treatment) despite persistence of epileptiform discharges. Again the authors cite studies of conditional (intestine-specific) SLC5A6 ko mice, with those viable (~1/3) demonstrating growth retardation, decreased boned density and GI abnormalities (similar to affected individuals). The phenotype could be rescued by oversupplementation of biotin and pantothenic acid (PMIDs cited: 23104561, 29669219). [Please consider inclusion in other relevant panels eg. metabolic disorders] Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.953 | DEGS1 |
Konstantinos Varvagiannis gene: DEGS1 was added gene: DEGS1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DEGS1 were set to 30620337; 30620338; 31186544 Phenotypes for gene: DEGS1 were set to Leukodystrophy hypomyelinating 18, MIM 618404) Penetrance for gene: DEGS1 were set to Complete Review for gene: DEGS1 was set to GREEN Added comment: Several individuals with biallelic pathogenic DEGS1 variants have been reported to date, in the following studies : [1] Pant et al. 2019 (PMID: 30620337) : 19 patients from 13 unrelated families [2] Karsai et al. 2019 (PMID: 30620338) : 1 individual [3] Dolgin et al. 2019 (PMID: 31186544) : 4 individuals belonging to a large consanguineous kindred As summarized in the first article and OMIM, affected individuals may have very poor psychomotor development, dystonia, spasticity, seizures with hypomyelinating leukodystrophy upon brain imaging and/or progressive atrophy of corpus callosum, thalami and cerebellum. Although a severe form overall was reported for many individuals in the first study, variable severity (eg. mild to severe ID) was reported among individuals belonging to the same kindred in the report by Dolgin et al. DEGS1 encodes Δ4-dehydroceramide desaturase which catalyzes conversion of dihydroceramide (DhCer) to ceramide (Cer) in the de novo ceramide biosynthetic pathway. Ceramide is the central unit of all sphingolipids, which are components of cellular membranes and play key roles in several processes incl. cell differentiation, neuronal signaling and myelin sheath formation. Sphingolipid balance is important for the CNS as demonstrated in the case of lysosomal disorders (eg. Gaucher, Niemann Pick, Farber) one enzymatic step away from DEGS1. Variants of all types (missense, stopgain, frameshift) have been reported with the majority/almost all located in the fatty acid desaturase (FAD) domain. Extensive studies have been carried out and demonstrated: - impaired DEGS1 activity in patients' fibroblasts and muscle suggested by increased DhCer/Cer ratio and compatible broader biochemical effects (higher levels of dihydrosphingosine, dihydrosphingomyelins, etc. and lower levels of sphingosine, monohexosylceramides, etc). - increased ROS production in patient fibroblasts (similar to a Drosophila model of excess DhCer), - high expression of the gene in child and adult CNS tissues from control individuals (evaluated by RT-qPCR in Ref. 1). A previous study has suggested that DEGS1 expression is upregulated during the 4-9th week of human embryogenesis (PMID cited: 20430792) which may suggest an important role for neural system development. - decreased expression for some variants either evaluated at the mRNA (RT-qPCR) / protein level (by Western Blot) - In zebrafish loss of Degs1 resulted in increased DhCer/Cer ratio, locomotor disability and impaired myelination similar to the patients' phenotype. Fingolimod, a sphingosine analog inhibiting Cer synthase (one step prior to DEGS1 in the de novo ceramide biosynthesis pathway, and converting sphingosine to ceramide in the salvage pathway) reduced the DhCer/Cer imbalance, ameliorated the locomotor phenotype and increased the number of myelinating oligodendrocytes in zebrafish, while it reduced the ROS levels in patient fibroblasts. Previous animal models: Apart from the zebrafish model (Pant et al.), higher DhCer/Cer ratios have been shown in homozygous Degs1 -/- mice similar to what is also observed in D. melanogaster. As summarized in MGI (and the previous studies as well) "mice homozygous for a knock-out allele exhibit premature death, decreased to absent ceramide levels, decreased body weight, scaly skin, sparse hair, tremors, hematological and blood chemistry abnormalities, decreased bone mineral content and density and decreased liver function." (PMIDs cited: 17339025, 28507162). ---- The respective OMIM entry is Leukodystrophy, hypomyelinating, 18 (#618404). DEGS1 is not associated with any phenotype in G2P. ---- As a result, DEGS1 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, sufficient number of individuals, supportive expression and biochemical studies, animal models, etc). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.800 | SNAP25 |
Konstantinos Varvagiannis gene: SNAP25 was added gene: SNAP25 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006 Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330 Penetrance for gene: SNAP25 were set to Complete Review for gene: SNAP25 was set to GREEN gene: SNAP25 was marked as current diagnostic Added comment: Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below): - Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent. - DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants. - Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant - Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant - Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant - Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported). Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified). SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID. SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.). Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988]. Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants. Animal models discussed: - Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238). - In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548). - Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108). - Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335). In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable). This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc). SNAP25 is among the genes discussed by Erger et al. (PMID: 30914295) as associated with ID in OMIM/HPO/G2P/SysID but not included in the current panel. As a result SNAP25 can be considered for inclusion in the ID panel probably as green (3 individuals with ID, role of SNARES in "synaptopathies", supportive animal models) or amber (if functional studies for individual variants would be required). Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.784 | BRSK2 |
Konstantinos Varvagiannis gene: BRSK2 was added gene: BRSK2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: BRSK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: BRSK2 were set to https://doi.org/10.1016/j.ajhg.2019.02.002 Phenotypes for gene: BRSK2 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality Penetrance for gene: BRSK2 were set to unknown Review for gene: BRSK2 was set to GREEN gene: BRSK2 was marked as current diagnostic Added comment: Hiatt et al. (2019 - https://doi.org/10.1016/j.ajhg.2019.02.002) report on 9 individuals, each with private heterozygous BRSK2 variant. Features included among others speech or motor delay, ID (8/9), ASD and variable behavioral anomalies. 6 variants predicted LoF (stopgain, frameshift or affecting splice-site) while 3 additional ones were missense (2 in the protein kinase domain and 1 in the kinase-associated 1 domain). In 6 individuals the variant had occurred as a de novo event while for 3 others parental samples were unavailable. Given the unknown inheritance, a single variant did not meet sufficient ACMG criteria to be classified as P/LP. All variants had in silico predictions supporting a deleterious effect and were absent from bravo database and gnomAD, where the gene appears to be relatively intolerant to protein-altering variation. As the authors note BRSK2 encodes a serine/threonine protein kinase involved in axonogenesis and polarization of cortical neurons. Although Brsk2- (or Brsk1-) knockout mice appear to be healthy and fertile, double knockouts for these genes resulted in pups with decreased spontaneous movement, poor response to tactile stimulation that died shortly after birth. In mice Brsk2 (and Brsk1) expression is restricted to the nervous system (PMID cited by the authors: 15705853) while in humans this gene is most highly expressed in brain (PMID cited: 23715323 - GTEx project). BRSK2 has been shown to interact with other neurodevelopmental genes eg. TSC2, PTEN, WDR45. Within the cohort of individuals studied, there was statistically significant enrichment for de novo BRSK2 variants when compared to the estimated backround mutation rate. Two further BRSK2 de novo protein-altering variants were previously reported in individuals with neurodevelopmental disorders (Iossifov et al. - PMID: 25363768 and DDD study - PMID: 28135719) although the missense variant in the latter study is also present in gnomAD database. BRSK2 is not associated with any phenotype in OMIM, nor in G2P. The gene is included in gene panels for ID offered by some diagnostic laboratories (eg. among those participating in the study). As a result, this gene can be considered for inclusion in the ID panel as green (or amber). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.595 | NUS1 |
Konstantinos Varvagiannis gene: NUS1 was added gene: NUS1 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: NUS1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: NUS1 were set to 25066056; 29100083; 24824130; 30348779 Phenotypes for gene: NUS1 were set to #617082 - ?Congenital disorder of glycosylation, type 1aa; #617831 - Mental retardation, autosomal dominant 55, with seizures; Abnormality of extrapyramidal motor function Penetrance for gene: NUS1 were set to unknown Review for gene: NUS1 was set to AMBER gene: NUS1 was marked as current diagnostic Added comment: Mutations in NUS1 have been implicated in recessive as well as dominant forms of ID (1 and 3 unrelated individuals respectively). The latter individuals presented with a developmental and epileptic encephalopathy with ID. At least 2 of these individuals had tremor and other movement disorders. A recent study proposes that NUS1 variants contribute to Parkinson's disease (1 individual with de novo variant affecting the canonical splice site, 26 additional individuals with missense variants - for which segregation studies where not however performed). ID is not commented on for these individuals. NUS1 is included in the DD panel of G2P, associated with "Epilepsy and intellectual disability". (Monoallelic LoF variants / Disease confidence : probable). This gene is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc). Associated phenotypes in OMIM and others discussed in the literature are summarized below (to my understanding). As a result, NUS1 can be considered for inclusion in the ID panel probably as amber. -------- Recessive - [MIM #617082 - ?Congenital disorder of glycosylation, type 1aa] : Park et al. (2014 - PMID: 25066056) report on an individual homozygous for a NUS1 missense variant (R290H) and suggest that biallelic variants cause a congenital disorder of glycosylation. The authors based in studies in yeast, mice and man provide evidence that NUS1 encodes the Nogo-B receptor (NgBR), a subunit of cis-prenyltransferase (cis-PTase), important for its activation. cis-PTase catalyzes one of the reactions for dolichol biosynthesis. Dolichol, in turn, is a carrier of glycans for N-linked glycosylation, O-mannosylation and GPI anchor biosynthesis. Genetic defects in the dolichol biosynthetic pathway have been linked to other forms of CDG and/or other recessive or dominant neurodevelopmental disorders (eg. SRD5A3- and DHDDS-related disorders). Similarities are provided at the cellular level between different organisms. Heterozygous knockout mice appear normal. Homozygosity is associated with embryonic lethality before E6.5. Conditional knockout in mouse embryonic fibroblasts led to accumulation of free cholesterol, decreased cis-PTase activity, and mannose incorporation in protein (the first & third rescued by transduction with lentiviral human NgBR). In patient fibroblasts protein levels appeared similar to controls. Interaction with Nogo-B (and hCIT - the product of DHDDS) was not affected. As in mice, accumulation of free cholesterol was observed in cells, with decreased cis-PTase activity and mannose incorporation. LAMP-1 and ICAM-1 were hypoglycosylated in patient fibroblasts. Altered dolichol profiles in serum and urine were observed in carriers of the NUS1 variant, similarly to what described in individuals with DHDDS LoF variants. ---------- Dominant - [MIM #617831 - Mental retardation, autosomal dominant 55, with seizures]. Hamdan et al. (2017 - PMID: 29100083) report on 3 unrelated individuals with developmental and epileptic encephalopathy (onset: 10m - 2.5y) and ID. Two individuals harbored de novo LoF variants while a third subject had a deletion of exon 2. Movement disorders were noted in all 3 and included tremor (2 subjects) or ataxia (1 additional subject). The authors cite a previous study on 6q22.1 deletions the critical region of which encompassed only NUS1 and the promoter of SLC35F1 (Szafranski et al. - PMID: 24824130). Haploinsufficiency is discussed as a possible mechanism (pLI of 0.87). A more severe phenotype due to dramatic reduction of NUS1 activity is proposed for the previously reported patient with CDG. ---------- Other: Guo et al. (2018 - PMID: 30348779) suggest that NUS1 pathogenic variants contribute to Parkinson's disease. By performing WES in 39 individuals with early onset Parkinson's disease and their unaffected patients (and sibs) the authors identified 1 individual with de novo insertion affecting a NUS1 canonical splice site. RT-PCR demonstrated increased mRNA levels compared with controls. Skipping of 91 bp of exon 3 was demonstrated. Study in 2 large sporadic PD-patient (N=1852+3237)/control cohorts (N=1565+2858) suggested association between NUS1 non-synonymous variants and PD (P=1.01e-5, OR:11.3). Other genetic causes of PD were excluded in 26 additional individuals with NUS1 missense variants. Phenotypes of all 27 individuals are provided in Dataset_S04. NUS1 has been found to be differentially expressed in PD mouse models. RNAi-mediated knockdown of Tango14 (the Drosophila NUS1) resulted in impaired climbing activity, reduction in brain dopamine levels and abnormal apoptotic signals in brain. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing | NOG | BRIDGE consortium edited their review of NOG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | NOG | Louise Daugherty classified NOG as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | NOG | Louise Daugherty commented on NOG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | NOG | BRIDGE consortium reviewed NOG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||