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Gene-disease assertions not curated here (add link or write note): AR Neurodevelopmental disorder with epilepsy and brain atrophy (https://www.omim.org/entry/619971)
Patient 2, PMID: 33833240: Mot maternally inherited, father deceased. Identified on exome. 15 yo M with developmental delay, profound ID, intractable seizures, abnormal EEG.
Patient V.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Male with Infantile spasms; Lip smacking, epilepsy/EEG, ID/DD, Microcephaly, skull and brain asymmetry, Plagiocephaly, scoliosis. Onset of symptoms 11 months.
Patient VI.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with seizures, ID/DD/ ataxia, myoclonus, prognathism. Onset of symptoms 12 months.
Patient VII.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with Epilepsy/EEG abnormalities, DD, ataxia. Onset of symptoms 5 months.
Patient VIII.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with Abnormal hand movements, epilepsy/EEG abnormalities, ID/DD, ataxia, Microcephaly, Severe dystonia. Onset of symptoms 2 months.
Patient IX.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with epilepsy/EEG abnormalities, ID/DD, ataxia, Microcephaly, Micrognathia, bitemporal narrowing, Optic atrophy. Onset of symptoms 2 months.
Patient P:X.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with epilepsy/EEG abnormalities, ID/DD, ataxia, myoclonus, Asymmetric volume loss throughout the left hemisphere on brain MRI. Onset of symptoms 6 months.
Patient P:XI.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Male with epilepsy/EEG abnormalities, ID/DD, ataxia, microcephaly. Onset of symptoms 3 months.
Patient P:XII.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Male with epilepsy/EEG abnormalities, ID/DD, Cerebral and cerebellar atrophy on brain MRI. Onset of symptoms 3 days.
PMID: 28135719: Two cases from the Deciphering Developmental Disorders project carried this variant, de novo in both patients.
Functional data, PMID: 33833240: Elevated lysosomal pH compared to WT in HEK293FT cell lines (Fig 3). Mouse lines with this variant had no notable abnormalities when the variant was in the heterozygous state but no homozygous pups were born. Authors predicted this variant caused LOF.
Further functional studies in cell lines - PMID: 34909687.
Patient III.1, PMID: 34909687: De novo, identified on exome and segregated via Sanger. Male with hypotonia, developmental delay, scoliosis, pectus carinatum, laryngomalacia (no epilepsy/EEG abnormalities). Onset of symptoms 4 months.
Patient IV.1, PMID: 34909687: De novo, identified on exome and segregated via Sanger. Male with developmental delay, Epilepsy/EEG abnormalities, ID, White-matter gliosis on brain MRI, Amelogenesis imperfecta, clubfoot. Onset of symptoms 7 months.
REVEL: 0.933.
Absent from gnomAD v4.
Not in ClinVar.
Scoring: missense (0.1) + de novo (0.5) = 0.6 points
Patient XIII.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Male with ID/DD, Microcephaly, simplified gyration, Prognathism. Onset of symptoms at 12 months.
Patient XIV.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Stillborn female with Micrognathia, hypertelorism.
Total: At least 7.1 points (stopped at moderate, there may be more information in the literature).
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
At least moderate.
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
Loss of function suggested but various mechanisms may be in play (see PMID: 37465367 Table 1)
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
Source:
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Pediatric.
Severity
Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited
ATP6V0A1 is associated with autosomal dominant developmental and epileptic encephalopathy. Individuals with this condition may have epilepsy, developmental delay, intellectual disability, ataxia, and microcephaly. Some individuals have been reported to have brain MRI abnormalities, scoliosis, hypotonia, myoclonus, and dysmorphic features. Although autosomal dominant inheritance appears to be more common, autosomal recessive inheritance has also been reported (PMID: 33833240, 34909687, 37465367).