SMCHD1
protein-codingstructural maintenance of chromosomes flexible hinge domain containing 1
Gene summary
This gene encodes a protein which contains a hinge region domain found in members of the SMC (structural maintenance of chromosomes) protein family. [provided by RefSeq, Dec 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~149.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0001347
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016393
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011323
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011323
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011323
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0011323
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011323
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011323
Submitter: ClinGen
The SMCHD1 gene is located on chromosome 18 at 18p11.32 and encodes the structural maintenance of chromosomes flexible hinge domain-containing protein 1, important in the structural maintenance of chromosomes. SMCHD1 was first reported in relation to autosomal dominant arhinia, choanal atresia, and microphthalmia in 2017 (Shaw et al., PMID: 28067909 and Gordon et al., PMID: 28067911). This disorder is characterized by nasal features of arrhinia or hypoplastic nose, choanal atresia, nasolacrimal duct stenosis, absent paranasal sinuses, and anosmia; ocular features comprising ano- or microphthalmia, uveal coloboma, and cataracts; other facial dysmorphisms such as high-arched or cleft palate, abnormal ears, hypoplastic maxilla, midface hypoplasia, and abnormal dentition; as well as defects of the reproductive axis including hypogonadotropic hypogonadism. Expressivity is variable and not every patient presents with all of these features. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the inheritance pattern and phenotypic variability, and to a lesser extent in the molecular mechanism. Therefore, the following disease entities have been kept as separate disease entities: arhinia, choanal atresia, and microphthalmia also known as Bosma-arhinia-microphthalmia-syndrome or BAMS (OMIM: 603457), and facioscapulohumeral muscular dystrophy 2 or FSHD2 (OMIM: 158901). Ten variants, all missense, that have been reported in 24 probands in 3 publications (PMIDs: 28067911, 28067909; Kinjo et al., 2020, PMID: 32620854) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has already been reached and exceeded. The mechanism of pathogenicity is inconclusive, with some evidence supporting loss of function and some evidence supporting gain of function. This gene-disease relationship is also supported by experimental evidence that includes animal models and in vitro functional assays (PMIDs: 28067911, 28067909; Gurzau et al., 2018, PMID: 29748383). Morpholino-mediated knockdown, as well as CRISPR/CAS9-mediated disruption of smchd1, in the zebrafish resulted in abnormal facial cartilage patterning, small eyes, and shorter projection length of the terminal nerve that contains exons of neurons expressing gonadotropin releasing hormone. These defects were rescued by full-length human wild-type but not variant SMCHD1 mRNA. Further, overexpression of either wild-type or variant human SMCHD1 mRNA in zebrafish did not produce any defects. This evidence suggests loss of function as the mechanism (PMID: 28067909). However, experiments in Xenopus embryos showed that while overexpression of wild-type human SMCHD1 mRNA did not produce any defects, overexpression of variant mRNA resulted in significantly smaller eyes and smaller nasal placodes, as well as a higher in invitro ATPase activity. This evidence is consistent with gain of function as the mechanism (PMIDs: 28067911, 29748383). In summary, the SMCHD1 gene is definitively associated with autosomal dominant arhinia, choanal atresia, and microphthalmia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 11.03.2021 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Musculoskeletal; Ophthalmologic
Intervention: Endocrine
Rationale: The condition involves hypogonadotropic hypogonadism, and in order to induce and maintain secondary sex characteristics, gradually increasing doses of gonadal steroids (females: estrogen/progestin; males: testosterone/hCG) can be beneficial; Related to fertility, endocrinologic therapy (females: recombinant hCG or pulsatile GnRH therapy; males: hCG/HMG/recombinant FSH or pulsatile GnRH therapy) may be effective, though IVF may be required
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMCHD1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_015295.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 26 | 302 | 6 | 335 | |
| missense | 18 | 9 | 752 | 43 | 1 | 823 |
| nonsense | 24 | 10 | 1 | 35 | ||
| start loss | 1 | 1 | ||||
| frameshift | 41 | 13 | 3 | 57 | ||
| splice donor/acceptor (+/-2bp) | 11 | 20 | 12 | 1 | 44 | |
| Total | 95 | 52 | 795 | 346 | 7 | 1295 |
Highest pathogenic variant AF is 0.0000065810254
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_056110.2 | 48 | MANE Select | |
| Ensembl | ENSP00000326603.7 | 48 | MANE Select | |
| Ensembl | ENSP00000463049.1 | 35 | Standard | |
| Ensembl | ENSP00000464684.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| smchd1 | Danio rerio | Structure: ethmoid cartilage Quality: decreased width abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- double-strand break repair
- dosage compensation by inactivation of X chromosome
- nose development
- positive regulation of DNA repair
- inactivation of X chromosome by heterochromatin assembly
Molecular Function
- DNA binding
- protein binding
- ATP binding
- ATPase activity
- protein homodimerization activity
Cellular Component
- nuclear chromosome, telomeric region
- Barr body
- site of double-strand break
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000320876
- Coding exons
- 48
- Length
- 149279
- Individuals with no LoFs
- 124617
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 19
- Defined
- 124636
- p
- 0.0000762
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.63 | 634 | 949 | 0.668 | 0.0000477 | 13124 |
| Missense (PolyPhen) | 116 | 344.4 | 0.33682 | 4768 | ||
| Synonymous | 0.800 | 302 | 320 | 0.943 | 0.0000162 | 3681 |
| Loss of Function | 8.56 | 9 | 102 | 0.0878 | 0.00000557 | 1395 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00013 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00031 | 0.00030 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00019 | 0.00019 | rare |
| European (Non-Finnish) | 0.000067 | 0.000062 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: 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:25294876, PubMed:24790221). Acts by promoting non-homologous end joining (NHEJ) and inhibiting homologous recombination (HR) repair (PubMed:25294876). {ECO:0000250|UniProtKB:Q6P5D8, ECO:0000269|PubMed:23143600, ECO:0000269|PubMed:23542155, ECO:0000269|PubMed:24790221, ECO:0000269|PubMed:25294876, ECO:0000269|PubMed:29748383}.;
- Disease
- DISEASE: Facioscapulohumeral muscular dystrophy 2 (FSHD2) [MIM:158901]: A degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles. {ECO:0000269|PubMed:23143600, ECO:0000269|PubMed:24075187, ECO:0000269|PubMed:24128691, ECO:0000269|PubMed:25256356, ECO:0000269|PubMed:25370034, ECO:0000269|PubMed:27059856, ECO:0000269|PubMed:28067911, ECO:0000269|PubMed:29748383}. Note=The disease is caused by mutations affecting the gene represented in this entry. SMCHD1 mutations lead to DUX4 expression in somatic tissues, including muscle cells, when an haplotype on chromosome 4 is permissive for DUX4 expression (PubMed:23143600). Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death (PubMed:23143600). FSHD2 and FSHD1 share a common pathophysiological pathway in which the FSHD2 gene SMCHD1 can act as a modifier for disease severity in families affected by FSHD1 (PubMed:24075187, PubMed:25370034). {ECO:0000269|PubMed:23143600, ECO:0000269|PubMed:24075187, ECO:0000269|PubMed:25370034}.; DISEASE: Bosma arhinia microphthalmia syndrome (BAMS) [MIM:603457]: An autosomal dominant syndrome characterized by severe hypoplasia of the nose, palatal abnormalities, hypoplasia of the eyes, sensory abnormalities of taste and smell, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence. {ECO:0000269|PubMed:28067909, ECO:0000269|PubMed:28067911, ECO:0000269|PubMed:29748383}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.114
Intolerance Scores
- LoFtool
- 0.236
- RVIS EVS
- -1.7
- RVIS percentile EVS
- 2.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.929
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |