MAU2 – Neurodevelopmental disorder

De novo microdeletions at chromosome 19p13.11p12 have been identified in five unrelated individuals presenting with neurodevelopmental disorders. Three of these deletions, ranging from 0.7 to 5.2 Mb, encompass the MAU2 locus and are absent in parental genomes, indicating a de novo occurrence (PMID:36379434). These patients consistently exhibited global developmental delay and atypical behavior.

Phenotypic spectrum in the three MAU2‐containing deletions included psychomotor delay, sleep disturbances, and variable malformations. Dysmorphic features were nonspecific, and congenital heart defects were noted in individuals with overlapping GDF1 deletions, suggesting locus‐specific effects with reduced penetrance (PMID:36379434).

The inheritance pattern for MAU2‐related neurodevelopmental disorder is autosomal dominant via haploinsufficiency due to de novo microdeletions. No families with inherited variants have been reported, and segregation analysis beyond proband–parent trios is lacking.

Genetic evidence includes three unrelated probands harbouring de novo microdeletions encompassing MAU2, providing moderate support for a causal role (PMID:36379434). The deletion types implicate loss‐of‐function as the underlying variant class.

Functional studies demonstrate MAU2’s critical role in cohesin loading through heterodimerization with NIPBL. Missense and in‐frame variants within the MAU2‐binding domain of NIPBL reduce MAU2 interaction and cohesin loading in vitro and in vivo (PMID:21934712, PMID:32433956), supporting a haploinsufficiency mechanism.

Integration of genetic and experimental data supports that MAU2 haploinsufficiency disrupts cohesin loader function, leading to neurodevelopmental impairment. Additional case reports beyond CNVs and extended segregation studies are warranted, but current evidence reaches a ClinGen Moderate level. Key take‐home: MAU2 haploinsufficiency via de novo deletion is a clinically actionable cause of autosomal dominant neurodevelopmental disorder.

References

• European journal of medical genetics • 2023 • Microdeletions at 19p13.11p12 in five individuals with neurodevelopmental delay. PMID:36379434
• European journal of human genetics : EJHG • 2012 • Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction. PMID:21934712
• Cell reports • 2020 • MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome. PMID:32433956

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