WDR37 – Neurooculocardiogenitourinary Syndrome

Neurooculocardiogenitourinary syndrome (NOCGUS) is a multisystemic disorder characterized by intellectual disability, seizures, ocular coloboma, cerebellar anomalies, and genitourinary malformations. Heterozygous de novo variants in WDR37 have now been reported as causative for NOCGUS (Neurooculocardiogenitourinary syndrome). Early evidence came from four unrelated probands with missense variants in the N-terminal region of WDR37 ([PMID:31327510]). Subsequent case series described three additional de novo missense variants in three unrelated individuals ([PMID:32530092]). Most recently, a de novo intronic 4-bp deletion, c.727-27_727-24del, was shown to cause aberrant splicing in a patient with classical and novel NOCGUS features, including anal atresia and polycystic kidney dysplasia ([PMID:38044197]). No reports have contradicted this gene–disease association, which is now supported by consistent clinical and molecular findings.

All reported WDR37 variants in NOCGUS act in an autosomal dominant manner with de novo occurrence in each case. Segregation beyond the proband has not been observed, and no inherited alleles have been described. Affected individuals manifest core features of intellectual disability (HP:0001249), coloboma (HP:0000589), seizure (HP:0001250), anal atresia (HP:0002023), and polycystic kidney dysplasia (HP:0000113), reinforcing a consistent phenotypic spectrum.

To date, eight unrelated de novo WDR37 variants have been documented: four missense changes affecting WD40-proximal residues (p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, p.Thr130Ile) and three clustering between WD40 repeats (p.Asp220Gly, p.Pro257His, p.Asp260Asn), plus one deep intronic deletion (c.727-27_727-24del). None of these variants are present in population databases, and they localize to highly conserved regions critical for WDR37 function.

Functional studies demonstrate that missense variants can alter protein stability or disrupt interactions. In vitro, the p.Asp220Gly mutant failed to bind PACS1 and PACS2 in co-immunoprecipitation assays, implicating loss of the WDR37–PACS axis ([PMID:34642815]). Splice assays for the c.727-27_727-24del variant confirmed 63-bp intron retention, predicting 21 aberrant residues that likely perturb WD repeat folding ([PMID:38044197]). In zebrafish, CRISPR-engineered missense alleles recapitulated growth defects and larval lethality, supporting a dominant-negative mechanism for these variants ([PMID:31327510]).

No conflicting evidence disputing the WDR37–NOCGUS association has been reported.

Collectively, eight de novo WDR37 variants in unrelated individuals, consistent segregation, and concordant functional data support a Strong clinical validity classification. Genetic evidence is Strong based on multiple de novo occurrences meeting ClinGen caps, and experimental work provides Moderate functional support. Screening for WDR37 variants is clinically valuable in patients with coloboma, neurodevelopmental impairment, seizures, and genitourinary anomalies, guiding diagnosis and management.

References

• American journal of human genetics • 2019 • De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome. PMID:31327510
• Clinical genetics • 2020 • Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants. PMID:32530092
• Human genetics • 2021 • WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins. PMID:34642815
• Brain & development • 2024 • Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome. PMID:38044197

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