SMCHD1 – Bosma Arhinia Microphthalmia Syndrome

Bosma Arhinia Microphthalmia Syndrome (BAMS; MONDO:0011323) is a rare congenital disorder characterized by complete or partial absence of the nose, microphthalmia, choanal atresia, anosmia, and hypogonadotropic hypogonadism. Pathogenic variants in the epigenetic regulator SMCHD1 have been established as the causal factor in BAMS, with heterozygous de novo missense mutations clustering in the extended GHKL-type ATPase domain.

Clinical Validity and Genetic Evidence

Multiple independent studies have identified a total of 55 unrelated BAMS probands harboring heterozygous SMCHD1 variants. Initial reports described 14 de novo missense mutations in 14 probands (PMID:28067911) and a subsequent cohort study confirmed 41 additional cases with similar variant clustering (PMID:31243061). Three recent singleton case reports further expand the phenotypic spectrum with novel variants in diverse populations (PMID:38555111; PMID:38773541; PMID:38808953). In all cases where parental DNA was available, variants arose de novo, supporting an autosomal dominant mechanism with full penetrance for the core craniofacial phenotype.

Variant Spectrum

To date, BAMS-associated SMCHD1 mutations are exclusively missense changes that localize within the extended ATPase domain. Representative variants include c.404G>A (p.Ser135Asn) and c.403A>T (p.Ser135Cys) that abolish normal enzymatic regulation and disrupt chromatin silencing in early nasal development (PMID:28067911). No recurrent or founder alleles have been reported, and the spectrum remains restricted to domain-specific gain-of-function changes.

Functional and Experimental Evidence

Biochemical assays demonstrate that BAMS-associated ATPase domain mutations confer elevated or aberrant hydrolysis activity in vitro, contrasting with loss-of-function variants seen in FSHD2 (PMID:29748383). In vivo studies using Xenopus laevis models show craniofacial defects and reduced eye size upon expression of human BAMS variants, mirroring patient phenotypes and confirming a gain-of-function pathogenic mechanism (PMID:28067911).

Integration and Clinical Utility

The consistent observation of de novo, heterozygous SMCHD1 missense variants in over 55 unrelated BAMS patients, combined with robust gain-of-function experimental data, establishes a definitive gene-disease association. SMCHD1 testing should be incorporated into diagnostic workflows for patients presenting with congenital arhinia and microphthalmia to facilitate early diagnosis, genetic counseling, and targeted management strategies.

References

• Nature Genetics • 2017 • De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. PMID:28067911
• Journal of Medical Genetics • 2019 • SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain. PMID:31243061
• The Journal of Biological Chemistry • 2018 • FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function. PMID:29748383
• Endocrinologia, diabetes y nutricion • 2024 • Clinical report of Bosma arhinia microphthalmia syndrome with a new variant on SMCHD1 gene. A case report. PMID:38555111
• BMC Medical Genomics • 2024 • Identification of a pathogenic SMCHD1 variant in a Chinese patient with bosma arhinia microphthalmia syndrome: a case report. PMID:38773541
• American Journal of Medical Genetics Part A • 2024 • Hemiarhinia caused by a missense variation in SMCHD1: A mild phenotype in the clinical spectrum of Bosma arhinia microphthalmia syndrome. PMID:38808953

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