A number sign (#) is used with this entry because of evidence that Cornelia de Lange syndrome-2 (CDLS2) is caused by mutation in the SMC1A gene (300040), which encodes a subunit of the cohesin complex, on chromosome Xp11.

Heterozygous mutation in the SMC1A gene can also cause developmental and epileptic encephalopathy with or without midline brain defects (DEE85; 301044), which only occurs in females and has a more severe phenotype.

Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. About 4 to 6% of patients have mutations in the X-linked SMC1A gene, whereas about 60% have mutations in the NIPBL gene (608667) on chromosome 5p13 (CDLS1; 122470) (summary by Musio et al., 2006, Hoppman-Chaney et al., 2012).

For a general phenotypic description and a discussion of genetic heterogeneity of Cornelia de Lange syndrome, see 122470.

Musio et al. (2006) reported 4 affected males with SMC1A mutations and similar CDLS symptoms: typical facial dysmorphisms, mental retardation in the moderate to severe range, and growth deficits with feeding problems in childhood. Their hands were not malformed, but the size of their hands was under the third percentile. Shortness of the first ray, clinodactyly of the fifth finger, and incomplete movement of the elbow were also evident. Three of the patients were related (2 sibs and their cousin). The sporadic patient and 1 of the related males showed severe gastroesophageal reflux. Three out of the 4 affected males had similar cerebral abnormalities on CT scan, with dilatation of cerebral ventricles and enlarged cisterna magna. The sporadic patient had severe epilepsy, and the 3 related males were subject to febrile seizures with abnormal electroencephalogram. The mother of the 2 affected sibs showed a very mild clinical phenotype and a slight impairment in cognitive development. Typical facial dysmorphism was very slight, and there was no record of growth problems or major malformations.

Limongelli et al. (2010) reported a 6-year-old girl with CDLS2 who carried a de novo heterozygous missense mutation in the SMC1A gene (I784T; 300040.0005). At birth and in infancy, she showed intrauterine growth retardation, developmental delay, and recurrent respiratory infections. Examination at age 6 years showed poor growth, microcephaly, synophrys, downslanting palpebral fissures, long and curly eyelashes, and thin vermilion of the upper lip. Echocardiography showed severe, concentric ventricular hypertrophy, with left ventricular outflow tract obstruction, mild aortic regurgitation, and mitral valve prolapse with mild mitral regurgitation.

Hoppman-Chaney et al. (2012) reported a 10-year-old girl with CDLS2. She presented at age 7 months with developmental delay and multiple congenital anomalies including hemihypertrophy of the right side and tetralogy of Fallot. She had very poor growth, with low weight and height, and microcephaly. Craniofacial features included marked microbrachycephaly, skull asymmetry with right-sided flattening, prominent metopic suture, and bitemporal narrowing. She had sparse hair, deep-set eyes, arched eyebrows, mild synophrys, slightly anteriorly rotated ears with long and narrow earlobes, full cheeks, smooth philtrum, small mandible, widely spaced teeth, esotropia, and mild coloboma of both upper lids. Other features included short neck, broad thorax with widely spaced nipples, scoliosis, and mild distal limb anomalies. She had profound developmental delay with inability to sit without support, spasticity, and lack of speech, but she did not have seizures. Brain MRI at age 13 months showed dysgenesis of the corpus callosum and semilobar holoprosencephaly, consistent with midline brain defects. A G-banded chromosome study at birth showed mosaic Turner syndrome: 45,X(7)/46,XX(23). In addition, array CGH performed later showed a de novo 8-kb deletion encompassing exon 13 to intron 16 of the SMC1A gene (300040.0006), resulting in an in-frame deletion of 126 amino acids and insertion of 3 novel amino acids. The mutant mRNA was expressed, and Hoppman-Chaney et al. (2012) concluded that the mutant protein lacking the coiled-coil domain would act in a dominant-negative manner.

The transmission pattern of CDLS2 in the family reported by Musio et al. (2006) was consistent with X-linked recessive inheritance in the males, although their carrier mother had mild features. However, hemizygous or heterozygous mutations in the SMC1A gene that were identified in a male patient with CDLS2 by Musio et al. (2006) and in a female patient with CDLS2 by Limongelli et al. (2010) occurred de novo.

Most CDLS2 patients with SMC1A mutations are female. The SMC1A gene usually escapes X-inactivation in females, suggesting that heterozygous mutations exert a dominant-negative effect in manifesting female carriers. Males with SMC1A mutations show a more severe phenotype than females with SMC1A mutations (summary by Hoppman-Chaney et al., 2012).

Musio et al. (2006) recruited 53 unrelated and 4 related individuals with a diagnosis of Cornelia de Lange syndrome, encompassing the entire spectrum of phenotypes. They found pathogenic NIPBL mutations in 24 of them, whereas the remaining 33 cases did not bear any NIPBL mutation. Of these 33 individuals, there was only 1 instance of familial occurrence, with 2 male sibs, their mother, and a first cousin affected. Affected individuals in this family were found to carry a hemizygous or heterozygous 3-bp deletion in the SMC1A gene (300040.0001). In addition, a male patient with sporadic occurrence of the disorder was found to have a de novo missense mutation in the SMC1A gene (E493A; 300040.0002).

Among 30 unrelated patients with CDLS, Pie et al. (2010) found that 11 (37%) patients had mutations in the NIPBL gene, consistent with CDLS1 (122470), and 3 (10%) had mutations in the SMC1A gene, with an overall molecular diagnostic yield of 47%. None of the patients had mutations in the SMC3 gene. Most of the patients were of Spanish origin. Although those with NIPBL mutations had a more severe phenotype than those with SMC1A mutations, the incidence of palate defects was higher in those with SMC1A mutations.