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Introduction

Cornelia de Lange Syndrome (CdLS) is multisystem disorder with intellectual disability and prenatal-onset growth retardation as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function (LOF) mutations in NIPBL. Mutations in genes which encode the other components of the sister chromatid cohesion system - SMC1A, HDAC8, RAD21 and SMC3 -cause less typical CdLS.

David FitzPatrick has been the medical director of the CdLS Foundation of UK and Ireland for the last 16 years and has had the privilege of getting to know many of the affected individuals and their families.

MRC HGU Study

We have studied 163 individuals with a CdLS or CdLS-like diagnosis who kindly agreed to take part in our research. All were screened for coding region mutations in known genes. 90 of these individuals also had genome-wide array-based comparative genomic hybridisation (aCGH) to look for missing or extra fragments of chromosomes. The entire NIPBL locus was sequenced in 19 trios. 5 screen-negative individuals were whole exome sequenced (looking at all the protein coding genes).

Causative mutations were identified in: Analysis of the clinical features

Comparison of growth data and scores of clinical severity and facial gestalt of the affected individuals respectively. Unlike typical CdLS, atypical CdLS shows marked locus heterogeneity with significant phenotypic overlap with other disorders of chromatin function. .

Medical Management of CdLS

Together with Dr Tonie Kline, the medical advisor for the US CdLS foundation we wrote a chapter for the book "Management of Genetic Syndromes" in 2010, the final draft of which can be access below

CdLS Medical Management Chapter