ZMYM2 – neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities

ZMYM2-related neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities (NECRC) is inherited in an autosomal dominant manner. A single proband (n=1 [PMID:37383123]) presented with global developmental delay, microcephaly, facial dysmorphism, hypotonia, and feeding difficulties. Whole-exome sequencing identified a heterozygous frameshift variant, c.2090_2091del (p.Ser697TrpfsTer3), in ZMYM2, implicating loss of normal protein function in NECRC pathogenesis.

Functional studies in congenital anomaly of the kidney and urinary tract (CAKUT) demonstrate that ZMYM2 loss-of-function causes renal and craniofacial defects in Xenopus morpholino knockdown and heterozygous mouse models, consistent with haploinsufficiency ([PMID:32891193]). These experiments confirm that truncated ZMYM2 proteins fail to rescue developmental phenotypes, supporting a LoF mechanism.

Key Take-home: ZMYM2 haploinsufficiency due to heterozygous frameshift variants causes NECRC, and early molecular diagnosis enables targeted management.

References

• World journal of clinical cases • 2023 • Novel mutation c.2090_2091del in neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities in an 18.5-mo-old boy: A case report. PMID:37383123
• American journal of human genetics • 2020 • Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations. PMID:32891193

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