Alternative titles; symbols
HGNC Approved Gene Symbol: SMCHD1
SNOMEDCT: 720511000;
Cytogenetic location: 18p11.32 Genomic coordinates (GRCh38) : 18:2,655,726-2,805,017 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18p11.32 | Bosma arhinia microphthalmia syndrome | 603457 | Autosomal dominant | 3 |
| Facioscapulohumeral muscular dystrophy 2, digenic | 158901 | Digenic dominant | 3 |
Proteins that contain a structural maintenance of chromosomes (SMC) hinge domain, such as SMCHD1, are typically involved in DNA management. SMCHD1 plays an essential role in X chromosome inactivation (Blewitt et al., 2008).
By sequencing clones obtained from a size-fractionated human brain cDNA library, Ishikawa et al. (1998) obtained a partial SMCHD1 clone, which they designated KIAA0650. RT-PCR analysis detected variable SMCHD1 expression in all tissues examined, with highest expression in testis, ovary, and lung.
Blewitt et al. (2008) cloned mouse Smchd1. The deduced 2,007-amino acid protein has an N-terminal ATPase domain and a C-terminal SMC hinge domain. Database analysis revealed orthologs in amphibians, birds, and eutherian and metatherian mammals. In female mouse embryonic fibroblasts, Smchd1 localized to the inactive X chromosome (Xi).
By histochemical staining of mouse embryos, Gordon et al. (2017) detected Smchd1 expression in the nasal placodes and optic vesicles at embryonic day (E) 9.5 and in the nasal epithelium at E12.5. The authors noted that in situ hybridization data indicated regional expression of Smchd1 in the nasal cavity in E14.5 mice, and that transcriptional profiling of mouse postnatal olfactory epithelium had shown that Smchd1 is specifically expressed in immature olfactory sensory neurons (Nickell et al., 2012).
By radiation hybrid analysis, Ishikawa et al. (1998) mapped the SMCHD1 gene to chromosome 18. Hartz (2012) mapped the SMCHD1 gene to chromosome 18p11.32 based on an alignment of the SMCHD1 sequence (GenBank AB014550) with the genomic sequence (GRCh37).
Blewitt et al. (2008) mapped the mouse Smchd1 gene to chromosome 17.
Gendrel et al. (2012) identified 3 major classes of CpG islands on Xi that showed rapid, intermediate, or slow methylation kinetics during X inactivation in mouse cells. A fourth class consisted of CpG islands on Xi for which methylation dynamics could not be assigned to any of the other classes. CpG islands with slow methylation kinetics were most common. CpG islands showing rapid or intermediate methylation kinetics had higher CpG density and GC content than those with slow methylation kinetics. Fast-methylating CpG islands were associated with fewer genes than slow-methylating CpG islands, and these genes were only weakly expressed in embryonic stem cells. Slow-methylating CpG islands were associated with low CpG density and higher levels of gene expression in embryonic stem cells than fast-methylating CpG islands. CpG islands with intermediate kinetics were located closer to the Xist locus relative to other classes. Use of knockout mouse embryonic fibroblasts revealed that Dnmt3b (602900), but not Dnmt3a (602769) or Dnmt3l (606588), was required for methylation of CpG islands of all classes. Smchd1 was required only for methylation of CpG islands with slow methylation kinetics. Smchd1 was not detected on Xi early during X inactivation, but was highly expressed throughout Xi late during X inactivation. Dnmt3b did not appear to be actively targeted to Xi.
Using CRISPR-Cas technology, Wang et al. (2018) generated Smchd1 -/- clones from a mouse hybrid cell line carrying 1 M. musculus X chromosome and 1 M. castaneus X chromosome. Loss of Smchd1 in mouse cells resulted in failure to silence a large subset of genes, termed 'Smchd1-sensitive genes' by the authors, on Xi. Analysis by allele-specific chromatin immunoprecipitation sequencing (ChIP-seq) showed that failure to silence Smchd1-sensitive genes correlated with an erosion of heterochromatin, indicating that Smchd1 regulates spreading of Xi heterochromatin. Loss of Smchd1 also resulted in regional defects in Xist RNA spreading. In situ high-throughput chromosome conformation capture revealed that the Xi in Smchd1 -/- cells contained unique new compartments, termed S1 and S2 compartments, that were different from the A and B compartments found on the active X chromosome (Xa). Characterization of these new compartments confirmed that Smchd1 played a critical role in organizing Xi structures by merging chromatin compartments. Xi in wildtype mouse cells contained weak but clearly discernible topologically associated domains (TADs) across the entire Xi. Depletion of Smchd1 led to Xi-specific strengthening of TADs, showing that Smchd1 controls TAD strength in an Xi-specific manner. Allele-specific ChIP-seq further demonstrated that Smchd1 suppressed binding of architectural factors to the Xi on a pan-Xi scale, as Ctcf (604167) and Rad21 (606462) exhibited increased binding to the Xi in Smchd1 -/- cells. Examination of Smchd1 genomic binding sites showed that Smchd1 was enriched in both gene-rich and gene-poor regions on Xi and bridged the S1 and S2 compartments. Further investigation demonstrated that S1 and S2 compartments occurred naturally, but only transiently, during de novo inactivation of the X chromosome before Smchd1 bound and facilitated Xist spreading in wildtype mouse cells. Upon recruitment of Smchd1, S1 and S2 compartments were merged by Smchd1 to create a compartmentless Xi, explaining why deletion of Smchd1 in mouse cells resulted in persistent S1 and S2 compartments.
Facioscapulohumeral Muscular Dystrophy 2
In affected members of 15 (79%) of 19 families with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Lemmers et al. (2012) identified heterozygous loss-of-function mutations in the SMCHD1 gene (see, e.g., 614982.0001-614982.0005). The mutations in 7 families were initially identified by exome sequencing and confirmed by Sanger sequencing. The mutational spectrum included small deletions, splice site mutations, and missense mutations, resulting in haploinsufficiency. Patients showed D4Z4 (see 606009) hypomethylation to levels less than 25% (normal being about 50%), and protein blot analysis in several patients showed decreased SMCHD1 protein in fibroblasts. Affected individuals were also heterozygous or homozygous for an FSHD1 (158900)-permissive D4Z4 haplotype that contains a polyadenylation signal to stabilize DUX4 (606009) mRNA in skeletal muscle. Primary myotubes from a normal individual with a normal-sized and methylated D4Z4 array on a permissive haplotype showed no DUX4 mRNA. However, decreasing SMCHD1 expression to about 50% using RNA interference resulted in transcriptional activation of DUX4 and a variegated pattern of DUX4 protein expression in the myotubes. The pattern of variegated DUX4 expression that resulted was similar to that observed in FSHD1 and FSHD2 myotube cultures. The findings indicated that SMCHD1 activity is necessary for D4Z4 hypermethylation and somatic repression of DUX4, and that reduction of SMCHD1 results in D4Z4 arrays that express DUX4 when a permissive haplotype is present. The SMCHD1 mutation and the permissive D4Z4 haplotype segregated independently in the families, indicating digenic inheritance. Of the 26 individuals with hypomethylation at D4Z4, a SMCHD1 mutation, and a permissive D4Z4 haplotype, 5 (19%) were asymptomatic, indicating incomplete penetrance. Lemmers et al. (2012) suggested that SMCHD1 mutations may modify the epigenetic repression of other genomic regions and the penetrance of other human diseases.
Sacconi et al. (2013) found that mutation in the SMCHD1 gene is a modifier of disease severity in families affected by FSHD1. Three unrelated families with intrafamilial clinical variability of the disorder were studied. In 1 family, a mildly affected man with FSHD1 carried a 9-unit D4Z4 repeat on a 4A allele with no SMCHD1 mutations, whereas his mildly affected wife carried a SMCHD1 mutation (T527M; 614982.0006) on a normal-sized 4A allele, consistent with FSHD2. Their more severely affected son and grandson each carried the 9-unit D4Z4 repeat on a 4A allele as well as the T527M SMCHD1 mutation, consistent with having both FSHD1 and FSHD2. In a second family, a man with a severe early-onset phenotype had both a 9-unit D4Z4 repeat on a 4A permissive allele and a mutation in the SMCHD1 gene. Each of his children, who had milder symptoms, inherited 1 of the genetic defects. In a third family, a man with a severe phenotype was also found to carry a 9-unit D4Z4 repeat on a 4A permissive allele with a SMCHD1 mutation. No information from his parents was available. Transduction of SMCHD1 shRNA into FSHD1 myotubes caused increased levels of DUX4 mRNA as well as transcriptional activation of known DUX4 target genes. These findings were consistent with further chromatin relaxation of the contracted FSHD1 repeat upon knockdown of SMCHD1. Sacconi et al. (2013) concluded that FSHD1 and FSHD2 share a common pathophysiologic pathway converging on transcriptional derepression of DUX4 in skeletal muscle.
Strafella et al. (2019) performed next-generation sequencing of the SMCHD1 gene in a cohort of patients with FSHD and identified 7 heterozygous pathogenic/likely pathogenic variants (see, e.g., 614982.0016-614982.0019) in 7 patients; 5 of the patients had a borderline D4Z4 fragment size (8-10 repeats) and 2 had a normal D4Z4 fragment size (more than 11 repeats). All 7 mutations were predicted to affect protein structure and conformation, resulting in loss of the GHKL-ATPase domain and/or the SMC hinge domain. Strafella et al. (2019) concluded that borderline D4Z4 size may be a risk factor or pathogenic modifier in patients with SMCHD1 mutations. Strafella et al. (2019) also identified 5 variants in the 3-prime UTR of the SMCHD1 gene, which were predicted to disrupt an existing miRNA binding site or to create a novel binding site for different miRNAs, suggesting a potential miRNA-dependent regulatory effect on associated pathways associated with FSHD.
Bosma Arhinia Microphthalmia Syndrome
By whole-genome, whole-exome, and targeted sequencing in 38 probands with Bosma arhinia microphthalmia syndrome (BAMS; 603457), Shaw et al. (2017) identified heterozygous missense mutations in the SMCHD1 gene in 32 (84%) of the probands (see, e.g., 614982.0007-614982.0015). The mutations all occurred within exons 3 to 13, spanning a GHKL-type ATPase domain. Experiments in zebrafish embryos suggested that the likely mode of action of the arhinia-associated alleles is loss of function. The authors observed largely identical methylation patterning at D4Z4 in arhinia and FSHD2 patients, and concluded that 2 completely distinct phenotypes can arise from deleterious changes in the same gene and even the same alleles. Noting the marked intrafamilial and interfamilial phenotypic variability in SMCHD1-mutated BAMS families, Shaw et al. (2017) suggested that BAMS-associated SMCHD1 variants are not fully penetrant and that such variants alone may not be sufficient to cause arhinia.
Simultaneously and independently, Gordon et al. (2017) performed whole-exome and/or Sanger sequencing in 14 probands with arhinia, 6 of whom were also studied by Shaw et al. (2017). They identified mutations in the SMCHD1 gene in all 14 probands (see, e.g., 614982.0008, 614982.0013, and 614982.0014). The mutations were shown to have occurred de novo in the 11 families for which DNA was available from the parents; all of the mutations occurred at highly conserved residues within the ATPase domain, and none was found in public variant databases. Gordon et al. (2017) noted that 6 of the 14 patients had mutations involving 3 adjacent amino acids (A134, S135, and E136; see, e.g., 614982.0013-614982.0015), and that 2 other mutations, H348R (614982.0008) and D420V were identified in 3 and 2 probands each, suggesting possible mutation hotspots. Analysis of patient methylation status showed a trend for hypomethylation compared to controls or unaffected family members; however, some patients with BAMS were normally methylated. In contrast to FSHD2-associated loss-of-function mutations (see 614982.0006), functional analysis of ATPase activity showed increased protein hydrolysis of ATP by 3 of the BAMS-associated mutants tested compared to wildtype SMCHD1 (see 614982.0013), and 1 BAMS variant showed unchanged ATPase activity. In addition, overexpression of BAMS-associated mutant SMCHD1 in Xenopus embryos resulted in tadpoles with noticeable craniofacial anomalies, including microphthalmia or anophthalmia, and eye diameters at 4 days postfertilization were significantly smaller in those embryos than in embryos with overexpression of wildtype SMCHD1 or an FSHD2-associated mutant. Gordon et al. (2017) concluded that BAMS-associated missense mutations might exhibit gain-of-function or neomorphic activity.
In an N-ethyl-N-nitrosourea mutagenesis screen, Blewitt et al. (2008) identified the modifier of murine metastable epialleles (MommeD1) mutation. Homozygosity for MommeD1 resulted in female-specific midgestation lethality and hypomethylation of the X-linked Hprt1 gene (308000) CpG island, suggesting a defect in X inactivation. Blewitt et al. (2008) found that the MommeD1 mutation resulted in a nonsense codon in exon 23 of the 48-exon Smchd1 gene. Homozygous mutant female embryos, but not male embryos, showed placental defects, with smaller trophoblast giant cell layer and smaller trophoblast giant cell nuclei. MommeD1 heterozygous female embryos showed delayed methylation at CpG islands, with normal methylation levels achieved by embryonic day 10.5. Smchd1 was not required for initial Xist expression, but it was required for subsequent DNA methylation and gene silencing on Xi.
Using facial cartilage patterning in zebrafish as a surrogate structure homologous to the human nose, Shaw et al. (2017) generated Smchd1-knockdown morphant zebrafish models and observed that all morphants exhibited narrowing of the ethmoid plate and an increase in the ceratohyal arch angle, both of which were dose-dependent phenomena, as well as delayed or absent development of ceratobranchial arches and microphthalmia. Ventral imaging revealed that morphant olfactory bulbs and hypothalami were intact, but the average projection length of the terminal nerve, where GnRH3 neurons reside, was reduced by 45% compared to controls. The cartilage, eye, and GnRH phenotypes were rescued by wildtype human SMCHD1 mRNA. CRISPR/Cas9-mediated genome editing recapitulated the craniofacial, ocular, and GnRH defects observed in the morphant models.
In a woman with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Lemmers et al. (2012) identified a heterozygous 5-bp deletion in exon 10 of the SMCHD1 gene (1302_1306del), resulting in a frameshift and premature termination (Y434X). The patient was also heterozygous for a permissive D4Z4 (see 606009) haplotype; D4Z4 methylation was decreased to 25% (normal is about 50%).
In a patient with FSHD2 (158901), Lemmers et al. (2012) identified a heterozygous 2068C-T transition in exon 16 of the SMCHD1 gene, resulting in a pro690-to-ser (P690S) substitution. The patient was also heterozygous for a permissive D4Z4 (see 606009) haplotype; D4Z4 methylation was decreased to 7%. The P690S mutation was inherited from the unaffected mother, who also had hypomethylation of D4Z4 (10%), but did not carry a permissive D4Z4 haplotype. The D4Z4 permissive haplotype was inherited from the unaffected father, who had normal D4Z4 methylation at 43%.
In 2 affected members of a 3-generation family with FSHD2 (158901), Lemmers et al. (2012) identified a heterozygous 1-bp deletion in exon 12 of the SMCHD1 gene, resulting in a frameshift and premature termination (Asp537IleIfsTer10). One affected individual was heterozygous for a permissive D4Z4 (see 606009) haplotype, whereas the other was homozygous for a D4Z4 permissive haplotype; D4Z4 methylation was decreased to 18 to 20% in the patients. The SMCHD1 mutation segregated with hypomethylation of D4Z4 in the family, and the D4Z4 permissive haplotype segregated independently. However, there were 4 apparently unaffected individuals with the SMCHD1 mutation, hypomethylation (11%), and a D4Z4 permissive haplotype, indicating incomplete penetrance. Western blot analysis of fibroblasts from 1 patient and 1 carrier showed decreased SMCHD1 levels.
In affected members of 2 families with FSHD2 (158901), Lemmers et al. (2012) identified a heterozygous G-to-A transition in intron 29 of the SMCHD1 gene (3801+1G-A), resulting in a splice site mutation. All patients were also either homozygous or heterozygous for a permissive D4Z4 (see 606009) haplotype. D4Z4 methylation in all patients was decreased to 5 to 16%.
In 4 affected members of 2 families with FSHD2 (158901), Lemmers et al. (2012) identified a heterozygous 4566G-A transition in exon 36 of the SMCHD1 gene, predicted to result in a synonymous thr1522-to-thr (T1522T) substitution. However, the mutation was demonstrated to cause aberrant splicing with the skipping of exon 36. Three affected individuals were also homozygous for a permissive D4Z4 (see 606009) haplotype; the fourth was heterozygous for a permissive D4Z4 haplotype. D4Z4 methylation in all patients was decreased to 13 to 23%. Western blot analysis of fibroblasts from 2 patients showed decreased SMCHD1 levels.
In a 3-generation family with FSHD2 (158901), Sacconi et al. (2013) identified a heterozygous c.1580C-T transition in exon 12 of the SMCHD1 gene, resulting in a thr527-to-met (T527M) substitution at a highly conserved residue. The mutation was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in in-house databases. The grandmother, who had a relatively mild phenotype, carried the T527M mutation on a normal-sized 4A D4Z4 allele (see 609009). Her son and grandson, who had earlier onset and a more severe phenotype, each carried both the T527M mutation as well as a contracted 9-unit D4Z4 allele on a permissive 4A haplotype, consistent with a diagnosis of both FSHD2 and FSHD1 (158900). The findings indicated that a SMCHD1 mutation and a D4Z4 contraction can act synergistically to cause additional derepression of the DUX4 gene and a more severe phenotype.
Gordon et al. (2017) analyzed the effects on ATPase activity of SMCHD1 variants and observed slightly decreased protein hydrolysis of ATP by the T527M mutant compared to wildtype SMCHD1.
In 2 sisters from a 3-generation German family (family O) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), originally reported by Thiele et al. (1996), Shaw et al. (2017) identified heterozygosity for a c.1034A-G transition (c.1034A-G, ENST00000320876.10) in exon 8 of the SMCHD1 gene, resulting in a gln345-to-arg (Q345R) substitution at a conserved residue within the GHKL-type ATPase domain. Their mother, who exhibited abnormal dentition, asymmetric nares, and anosmia, was also heterozygous for the mutation, as was their maternal grandmother, who showed only abnormal dentition and asymmetric nares.
In 7 sporadic patients with Bosma arhinia microphthalmia syndrome (BAMS; 603457), including a Norwegian girl (patient L1) originally reported by Olsen et al. (2001), a Caucasian man (patient F1) previously reported by Graham and Lee (2006) as 'patient 1,' and a Mexican boy (patient Z1) described by Becerra-Solano et al. (2016), Shaw et al. (2017) identified heterozygosity for a c.1043A-G transition (c.1043A-G, ENST00000320876.10) in exon 9 of the SMCHD1 gene, resulting in a his348-to-arg (H348R) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation segregated with disease in the 4 families for which DNA was available from other family members, and it was shown to have arisen de novo in the probands from 3 of those families.
Gordon et al. (2017) independently studied 2 of the patients reported by Shaw et al. (2017), the Norwegian girl (patient L1) and a Chinese boy (patient N1), as well as an affected Ukrainian girl, and identified the H348R mutation in all 3 patients; analysis of parental DNA in the Chinese family demonstrated that the mutation arose de novo in the proband. Gordon et al. (2017) noted that the H348R variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases. Overexpression of the H348R mutant in Xenopus embryos resulted in significantly smaller eye diameter than overexpression of wildtype SMCHD1 or an FSHD2-associated mutant.
In 4 unrelated probands with Bosma arhinia microphthalmia syndrome (BAMS; 603457), including a patient (patient E1) originally reported by Gifford et al. (1972) and also studied by Bosma et al. (1981), and another patient (patient C1) previously described by Tryggestad et al. (2013), Shaw et al. (2017) identified heterozygosity for a c.423G-C transversion (c.423G-C, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a leu141-to-phe (L141F) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation segregated with disease in the 2 families for which DNA was available from other family members, and was shown to have arisen de novo in a Swiss boy (patient V1). The authors noted that 1 of the patients (C1) did not exhibit the complete 'Bosma triad,' since he had arhinia and hypogonadism, but not microphthalmia.
In an 11-year-old Caucasian Hispanic girl (patient AH1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), Shaw et al. (2017) identified heterozygosity for a c.1199A-T transversion (c.1199A-T, ENST00000320876.10) in exon 10 of the SMCHD1 gene, resulting in a gln400-to-leu (Q400L) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was also present in the proband's half sister, who had a hypoplastic nose, and in their father, who exhibited only anosmia.
In a 46-year-old Caucasian man (patient T1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), originally reported by Brasseur et al. (2016), Shaw et al. (2017) identified heterozygosity for a c.408A-C transversion (c.408A-C, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a glu136-to-asp (E136D) substitution at a highly conserved residue within the GHKL-type ATPase domain. The proband's father, who had been diagnosed with limb/girdle muscular dystrophy but exhibited no apparent facial dysmorphism and had no history of vision abnormalities or anosmia, was also heterozygous for the mutation, which was not found in the proband's unaffected mother. DNA was unavailable for the paternal grandmother and great-aunt, who were reported to have colobomata, or a paternal great-uncle, who was born blind.
In a 17-year-old African American girl (patient AG1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), Shaw et al. (2017) identified heterozygosity for a c.410G-A transition (c.410G-A, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a gly137-to-glu (G137E) substitution at a highly conserved residue within the GHKL-type ATPase domain. Shaw et al. (2017) noted that the G137E mutation had previously been reported in a patient with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901) by Lemmers et al. (2012).
In a 28-year-old German woman (patient M1) and a 3-year-old Irish girl (patient AF1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), originally reported by Muhlbauer et al. (1993) and Courtney et al. (2014), respectively, Shaw et al. (2017) and Gordon et al. (2017) independently identified heterozygosity for a c.403A-T transversion (c.403A-T, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-cys (S135C) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was not found in the unaffected parents from either family, indicating that it arose de novo in both probands; Gordon et al. (2017) stated that the variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases. Fibroblasts from patient M1 showed no defects in the DNA damage response or impaired nonhomologous end joining. ATPase assays demonstrated increased protein hydrolysis of ATP with the S135C mutant compared to wildtype. Gordon et al. (2017) concluded that S135C represents a gain-of-function variant.
In a German woman (patient R1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), who was 1 of 2 affected sisters originally reported by Ruprecht and Majewski (1978), and in an unrelated affected Caucasian man (patient I1), Shaw et al. (2017) identified heterozygosity for a c.404G-A transition (c.404G-A, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-asn (S135N) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was shown to have arisen de novo in the male proband, as it was not found in his unaffected parents; it was also not found in his 2 unaffected sisters.
Gordon et al. (2017) independently identified the S135N mutation in a 4-year-old North African boy with BAMS, in whom it arose de novo; they stated that the variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases.
In a 4-year-old boy (patient AK1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), Shaw et al. (2017) identified heterozygosity for a de novo c.404G-T transversion (c.404G-T, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-ile (S135I) substitution at a highly conserved residue within the GHKL-type ATPase domain.
In a 28-year-old patient (patient I) with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Strafella et al. (2019) identified heterozygosity for a 2-bp duplication (c.182_183dupGT, NM_015295.2) in exon 1 of the SMCHD1 gene, predicted to result in a frameshift and premature termination (Gln62ValfsTer48). The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the ExAC, gnomAD, and 1000 Genomes Project databases. The mutation was predicted to result in nonsense-mediated mRNA decay, a truncated protein lacking the essential functional GHKL-ATPase and SMC hinge domains, and/or disruption of normal splicing. The patient was also heterozygous for a D4Z4 (606009) repeat size of 10 repeated units. Functional studies were not performed.
In a 52-year-old patient (patient III) with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Strafella et al. (2019) identified heterozygosity for a c.3469G-T transversion (c.3469G-T, NM_015295.2) in exon 27 of the SMCHD1 gene, predicted to result in a gly1157-to-ter (G1157X) substitution. The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the 1000 Genomes Project, ExAC, and gnomAD databases. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal SMC hinge domain and consequent disruption of protein secondary structure. The patient was also heterozygous for a D4Z4 (606009) repeat size of 8 units. Functional studies were not performed.
In a 62-year-old patient (patient V) with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Strafella et al. (2019) identified heterozygosity for a 2-bp deletion (c.5150_5051delAA, NM_015295.2) in exon 41 of the SMCHD1 gene, predicted to result in a frameshift and premature termination (Lys1717ArgfsTer16). The mutation was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal SMC hinge domain. The patient was found to have a normal D4Z4 (606009) repeat size of more than 11 repeated units. Functional studies were not performed. This patient was previously reported by Cascella et al. (2018).
In a 73-year-old patient (patient II) with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Strafella et al. (2019) identified heterozygosity for a 1-bp duplication (c.2129dupC, NM_015295.2) in exon 16 of the SMCHD1 gene, predicted to result in a frameshift and a premature termination codon (Ala711CysfsTer11). The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the 1000 Genomes Project, ExAC, and gnomAD databases. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal hinge domain. The patient was also heterozygous for a D4Z4 (606009) repeat size of 9 repeated units. Functional studies were not performed.
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