Disease linkage

An X-linked form of the disorder Cornelia de Lange syndrome can be caused by mutations in the SMCa1 gene (OMIM). Cornelia de Langes syndrome is a developmental disorder which affects many parts of the body, and is most often recognized on the basis of characteristic facies, such as low anterior hairline, synophrys, anteverted nares, maxillary prognathism, long philtrum, 'carp' mouth in association with prenatal and postnatal growth retardation, mental retardation and, in many cases, upper limb anomalies. This syndrome is in most cases (around 50%) caused by a mutation in the NIPBL gene, which also encodes a part of the cohesin complex. However, in 2006 Musio et al. reported 4 affected males with SMCA1 mutations and many of the major features of Cornelia de Langes syndrome such as the typical facial dysmorphisms, mental retardation in the moderate to severe range, and growth deficits with feeding problems in childhood. However, the symptoms were not as severe as the ones observed in patients with NIPBL mutations, for example their hands were not malformed but the size of their hands were under the third percentile.

One patient was sporadic, the other three were related, two siblings and one cousin. The mother of the two affected siblings showed a mild clinical phenotype. In the two brothers and their cousin a 3-nt deletion at nucleotide 2493-2495 in the cDNA (accession number S78271 in genBank) was observed. This resulted in a deletion of Q832 and a D831E substitution. We haven't been able to confirm these changes, since the authors didn't mention the accession number to the original sequence. When comparing the sequence to which they linked (S78271, GenBank) with the wild type mRNA sequence (NM_006306, GenBank) using ClustalW other differences than the ones described in the article was found. This was probably due to comparing to another wt sequence than the one the authors used.

In the case where Cornelia de Langes syndrome was sporadic an A-to-C transversion at nucleotide 1478 of the cDNA sequence, which caused an E493A missense mutation, was found. This mutation was not found in the patients unaffected brother or sister. The effect of this mutation is probably damaging, according to PolyPhen (not controlled).

Deardorff et al. identified 14 additional SMC1A mutations in patients with a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Analysis of the mutant SMC1A proteins indicated that they were likely to produce functional cohesin complexes; however, Deardorff et al. (2007) posited that they mutations may alter their chromosome binding dynamics.

(Interesting note: SOX2 has been excluded as a candidate for Cornelia de Lange Syndrome)

Musio et al. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations, Nature Genetics 2006 May;38(5):528-30. Epub 2006 Apr 9

Deardorff et al. ( Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Am. J. Hum. Genet. 80: 485-494, 2007)

X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations, Nature Genetics 2006 May;38(5):528-30. Epub 2006 Apr 9

http://ghr.nlm.nih.gov/condition=corneliadelangesyndrome + OMIM