WDR73 Gene Curation
- Andrea Oza
Analytics
Gene-disease assertions not curated here (add link or write note):
Disease | Galloway-Mowat syndrome |
|---|---|
Inheritance | Autosomal recessive |
Prevalence |
Source: |
Rapid or full curation? | Rapid Full |
ClinGen - none. GenCC - Strong (Invitae). Babyseq - none. HGMD - curated select variants below. | |
Clinical Validity Scoring Notes and points | c.703C>T p.Q235* - 0.0006% (13/1177596) Eur gnomAD, NMD+. PMID:25873735 (2015) - two siblings from a consanguineous family with severe global developmental delay, intellectual disability, hypoplasia of the cerebellum and biochemical findings suggestive of nephrotic disease. Variants found via WES and Parents confirmed het, 1 unaffected sib het. Zebrafish knockdown showed brain growth and morphogenesis defects. Segregations, ANIMAL MODEL 2 POINT, 2 VARIANT POINTS C.129T>G TYR42* (aka Tyr43*) - 1 allele gnomAD, NMD+. PMID: 25466283 (2014): Family A - two homozygous sibs, parents are both het. Clinical features include nephrotic syndrome, FSGS, ESKD at 5 years, secondary microcephaly, peripheral hypertonia, axial hypotonia, nystagmus, epileptic spasms, ID, cerebellar atrophy, thin corpus callosum, facial dysmorphism, optic atrophy. Cultured fibroblasts from patient A showed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. FUNCTIONAL ALTERATION PATIENT CELLS 1 POINT, 1 seg, 2 VARIANT POINTS c.766dupC p.Arg256Profs*18 - NMD+, 0.0006% (13/1178688) Eur gAD v4. PMID: 25466283 (2014) in family B, hom in affected individual, parents and unaffected sib are het. Nephrotic syndrome, FSGS, microcpharly, hypertonia, ID, spasticity, cerebellar atrophy, thin corpus callosum, facial dysmorphism, optic atrophy. IHC staining showed expression in human fetal kidney and brain. 1 POINT EXPRESSION, 2 VARIANT POINTS c.400_401delAG p.(Trp136Alafs*2). 3 alleles gnomAD, NMD+. FROM PMID: 26123727 (2015): In family 1, HOM in two sibs with cerebellar atrophy, ID, axial hypotonia, ataxia, dystonia, microcephaly, irregular sleep pattern, feeding problems, brain atrophy, optic atrophy, retinopathy, no renal involvement at age 11y. 2 VARIANT POINTS, 1 seg. total segregations: 3 affected, 2 unaffected - eLOD 2.056, 1 POINT SEG Replication over 3 years (first paper scored in 2014). PMID: 30315938 from 2018 reports c.767G>A R256Q (10 alleles gnomAD). All variants in this section are rare enough for a rare AR disease.
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Clinical Validity Points Total | 13
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Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive. Source: 25873735, 25466283, 25466283, 26123727, 30315938 |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function See clinical validity scoring. PMID: 25873735, 25466283, 25466283, 26123727
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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 | Severe |
Clinical Features | neurodegenerative disorder characterized by infantile onset of microcephaly and central nervous system abnormalities resulting in severely delayed psychomotor development. Brain imaging shows cerebellar atrophy and sometimes cerebral atrophy. More variable features include optic atrophy, movement disorders, seizures, and nephrotic syndrome Sources: 26123727 |
HPO Terms |
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Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary | The WDR73 gene is associated with autosomal recessive Galloway-Mowat syndrome, which is characterized by microcephaly with brain anomalies such as cerebellar atrophy, intellectual disability, and early-onset nephrotic syndrome. Additional features may include optic atrophy, seizures, strabismus, and short stature. |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza D-210811480-BH-4021-P-A 01.02.2024 |