Recurrent mutations could delineate clusters for genotype–phenotype correlations that may either predict disease outcome and evolution, or disclose the actions of modifiers. However, more patients need to be characterized to detail SMC1A allelic heterogeneity and to pinpoint the mutations responsible for the phenotypes observed at the extremes of the clinical spectrum. Some degree of cognitive impairment is the unifying feature of both entities. In comparison with NIPBL, the clinical spectrum underpinned by SMC1A mutations generally includes fewer structural anomalies, no upper limb reduction, milder facial dysmorphisms, and attenuated growth delay. Interference with cohesin binding to DNA has been demonstrated for SMC1A mutations mapping to the coiled-coil/hinge junctions, and a trend toward increased sensitivity to DNA damage has been described in most investigated patients' cell lines. The hinge dimerization domain and the crucial functional motifs of the N- and C-terminal ABC cassettes are spared. A few generalities about life-permissive SMC1A mutations have emerged, which are invariably missense and in-frame deletions and that apparently affect all the following protein domains: the N- and C-ATP-binding heads, the coiled-coils, and the coiled-coil/hinge junctions. To date, 44 CdLS individuals harboring 29 unique SMC1A mutations (23 missense and six in-frame deletions) have been described: 33 sporadic and 11 belonging to four families, with a 2:1 female:male ratio (29 females and 14 males plus one patient whose sex was not specified). Mutations in SMC1A (Structural Maintenance of Chromosomes 1A) (OMIM 300040), located at Xp11.22 and reported to escape X-inactivation in humans, account for about 5% of clinically diagnosed CdLS patients who are characterized by phenotypic features similar to, but usually milder than those of the much more numerous (up to 65%) CdLS patients with NIBPL mutations. As there is such broad clinical expressivity, the term “cohesinopathy” is currently preferred, especially for the recently identified entities that partially overlap with CdLS. The spectrum of clinical presentation ranges from mild to severe intellectual disability, malformations affecting one to multiple systems with upper limb reduction in a subset of cases, and characteristic slight or pronounced facial dysmorphisms (synophrys, long eyelashes, anteverted nostrils, thin upper lip vermilion, and micrognathia). © 2013 Wiley Periodicals, Inc.Ĭornelia de Lange syndrome (CdLS OMIM 122470, 300590, 610759, 614701, and 300882) is a clinically and genetically heterogeneous neurodevelopmental disorder caused by mutations in genes encoding subunits ( SMC1A, SMC3, and RAD21) or regulators ( NIPBL and HDAC8) of the cohesin complex. Our clinical and molecular findings expand the total number of characterized SMC1A-mutated patients (from 44 to 52) and the restricted repertoire of SMC1A mutations (from 29 to 34), contributing to the molecular and clinical signature of SMC1A-based CdLS. This raises the issue of gender effect when addressing mutation-phenotype correlation for genes such as SMC1A, which incompletely escapes X-inactivation. p.V651M was found in the only male individual of our cohort, who presented with the most severe phenotype. All mutations except p.V651M were scored as pathogenic by three or four of the tools. The effect of the mutations on SMC1A protein function has been predicted using four bioinformatic tools. The latter is localized in the H-loop, and represents the first mutation involving a functional motif of SMC1A protein. The following novel missense mutations, all affecting highly conserved amino acid residues, were found: p.R398G in the N-terminal coiled-coil domain, p.V651M in the C-terminal coiled-coil/hinge junction, p.R693G in the C-terminal coiled-coil, and p.N1166T and p.L1189F in the C-terminal ABC cassette. Comparison of pairs of individuals with the same mutation indicates only partial overlap of their clinical phenotypes. The other three have been reported each in a single case. Five of the eight mutations are novel, with two involving amino acid residues previously described as altered in a different way. We report on the clinical and molecular characterization of eight patients, one male and seven females, with clinical diagnosis of Cornelia de Lange syndrome (CdLS), who were found to carry distinct mutations of the SMC1A gene.
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