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| Intellectual disability - microarray and sequencing v3.0 | NUS1 |
Konstantinos Varvagiannis edited their review of gene: NUS1: Added comment: Please consider upgrading this gene (NUS1 is also rated Green in the epilepsy panel). Den et al (2019 - PMID: 31656175) reported on 2 additional unrelated individuals (aged 17 and 59y) both presenting intellectual disability, epilepsy , involuntary movements, ataxia and scoliosis. Both were found to harbor the same splicing variant in NUS1 (NM_138459.4:c.691+1C>A) following exome sequencing. Using lymphoblastoid cell lines from both individuals it was demonstrated that the variant creates a new splice donor site in exon 3 further creating a new reading frame and producing a premature termination codon [c.601_691del or p.(Arg202Glnfs*9)]. Using cyclohexamide, it was further shown that the mutant mRNA is partially subjected to NMD. [Additional variants identified by exome for the 2 subjects were non diagnostic (/VUS). An SPTAN1 nonsense variant identified in one was inherited from an unaffected parent (dominant-negative mechanism listed in G2P for this gene / in ClinVar all pLoF variants are submitted as VUS)]. -----; Changed rating: GREEN; Changed publications: 25066056, 29100083, 24824130, 30348779, 31656175 |
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| Intellectual disability - microarray and sequencing v2.1098 | NSF |
Konstantinos Varvagiannis gene: NSF was added gene: NSF was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NSF were set to 31675180 Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability Penetrance for gene: NSF were set to unknown Mode of pathogenicity for gene: NSF 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: NSF was set to AMBER Added comment: Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed). Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1098 | FDFT1 |
Konstantinos Varvagiannis gene: FDFT1 was added gene: FDFT1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FDFT1 were set to 29909962 Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face Penetrance for gene: FDFT1 were set to Complete Review for gene: FDFT1 was set to AMBER Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below]. ---- Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families. The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias). FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis. A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites. Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis). WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included: - Minigene splice assay demonstrating retention of 22 bp in intron 8. - Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts) - Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot. Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected). As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant : - cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect. - Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity. Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure. In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories. Sources: Literature |
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| Intellectual disability - microarray and sequencing v2.1062 | TDP2 |
Konstantinos Varvagiannis gene: TDP2 was added gene: TDP2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TDP2 were set to 24658003; 30109272; 31410782 Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949) Penetrance for gene: TDP2 were set to unknown Review for gene: TDP2 was set to GREEN gene: TDP2 was marked as current diagnostic Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder. TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity. The gene is expressed in fetal and adult human brain. Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role. Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes. Published studies are summarized below. TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID. Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model). ------------ [1] - PMID: 24658003 (Gómez-Herreros et al. 2014): Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3). A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study). The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity). The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject. As also commented: - TDP2 has relevant expression in human (particularly adult) brain. - Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated. - Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968). [2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018): A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle). [3] - PMID: 31410782 (Ciaccio et al. 2019): A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing. Sources: Literature, Radboud University Medical Center, Nijmegen |
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| Intellectual disability - microarray and sequencing v2.1047 | 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 |
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| Intellectual disability - microarray and sequencing v2.592 | HEXA | Louise Daugherty Phenotypes for gene: HEXA were changed from Tay-Sachs disease, 272800GM2-gangliosidosis, several forms, 272800[Hex A pseudodeficiency], 272800; GM2-GANGLIOSIDOSIS TYPE 1 (GM2G1) to Tay-Sachs disease, 272800; GM2-gangliosidosis, several forms, 272800; GM2-GANGLIOSIDOSIS TYPE 1 (GM2G1) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | HEXA | BRIDGE consortium edited their review of HEXA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | HEXA | BRIDGE consortium edited their review of HEXA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability - microarray and sequencing | HEXA | BRIDGE consortium reviewed HEXA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||