CHRNA7 – Complex Neurodevelopmental Disorder

A homozygous 15q13.3 microdeletion including CHRNA7 was identified in a boy with complex neurodevelopmental disorder characterized by hypotonia (HP:0001252), severely reduced visual acuity (HP:0001141), profound intellectual disability (HP:0002187) and refractory epilepsy. The deletion spans multiple genes (TRPM1, CHRNA7, MTMR10, FAN1), with absence of CHRNA7 proposed to underlie the seizures and cognitive impairment (PMID:20425840). Inheritance is autosomal recessive, but no additional affected families or segregation data have been reported, limiting genetic evidence to this single proband (PMID:20425840).

Functional assessment of a CHRNA7 missense variant, c.1267G>A (p.Gly423Ser), expressed in Xenopus laevis oocytes shows protein kinase C–dependent promotion of receptor desensitization, supporting a loss-of-function mechanism for CHRNA7 variants (PMID:17132684). While this aligns with the proposed pathogenic mechanism of CHRNA7 haploinsufficiency in neuronal excitability and cognition, additional autosomal recessive cases and segregation studies are needed to confirm causality. Key take-home: CHRNA7 loss should be considered in autosomal recessive complex neurodevelopmental disorders presenting with epilepsy and severe intellectual disability.

References

• American Journal of Medical Genetics Part A • 2010 • A 15q13.3 homozygous microdeletion associated with a severe neurodevelopmental disorder suggests putative functions of the TRPM1, CHRNA7, and other homozygously deleted genes. PMID:20425840
• Molecular Pharmacology • 2007 • Novel G423S mutation of human alpha7 nicotinic receptor promotes agonist-induced desensitization by a protein kinase C-dependent mechanism. PMID:17132684

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