SMCHD1

Chr 18ADDigenic dominant

structural maintenance of chromosomes flexible hinge domain containing 1

ENSG00000101596 UniProt: A6NHR9 OMIM: 614982

The protein is a non-canonical structural maintenance of chromosomes (SMC) family member that regulates chromatin architecture through epigenetic silencing, promotes heterochromatin formation and X chromosome inactivation, and participates in DNA double-strand break repair. Mutations cause Bosma arhinia microphthalmia syndrome and facioscapulohumeral muscular dystrophy 2 (digenic form), following autosomal dominant or digenic dominant inheritance patterns. The gene is highly constrained against loss-of-function variants, reflecting its essential cellular functions.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture (By similarity). Promotes heterochromatin formation in both autosomes and chromosome X, probably by mediating the merge of chromatin compartments (By similarity). Plays a key role in chromosome X inactivation in females by promoting the spreading of heterochromatin (PubMed:23542155). Recruited to inactivated chromosome X by Xist RNA and acts by mediating the merge of chromatin compartments: promotes random chromatin interactions that span the boundaries of existing structures, leading to create a compartment-less architecture typical of inactivated chromosome X (By similarity). Required to facilitate Xist RNA spreading (By similarity). Also required for silencing of a subset of clustered autosomal loci in somatic cells, such as the DUX4 locus (PubMed:23143600). Has ATPase activity; may participate in structural manipulation of chromatin in an ATP-dependent manner as part of its role in gene expression regulation (PubMed:29748383). Also plays a role in DNA repair: localizes to sites of DNA double-strand breaks in response to DNA damage to promote the repair of DNA double-strand breaks (PubMed:24790221, PubMed:25294876). Acts by promoting non-homologous end joining (NHEJ) and inhibiting homologous recombination (HR) repair (PubMed:25294876)

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/Digenic dominantLOEUF 0.152 OMIM phenotypes

Clinical Summary— SMCHD1

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Gene-Disease Validity (ClinGen)

arhinia, choanal atresia, and microphthalmia · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.15LOEUF

pLI 1.000

Z-score 8.56

OE 0.09 (0.05–0.15)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.63Z-score

OE missense 0.67 (0.63–0.71)

634 obs / 948.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.15)

0≤0.351.4

Missense OE?0.67 (0.63–0.71)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 9 / 102.5Missense obs/exp: 634 / 948.8Syn Z: 0.80

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSMCHD1-related isolated arhinia/Bosma arhinia syndromeOTHERAD

This gene — mechanism propensity

0.2997th %ile

GOF

0.2895th %ile

LOF

0.66top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.15

GOF1 literature citation

Literature Evidence

GOFBiochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 21

LOFTogether, these results support haploinsufficiency of SMCHD1 as a cause of D4Z4 hypomethylation in unrelated FSHD2 kindreds.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References