Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a mutation in the gene encoding the complementary subunit of the cohesin heterodimer, SMC3, and 14 additional SMC1A mutations. All mutations are predicted to retain an open reading frame, and no truncating mutations were identified. Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics. Our data indicate that SMC3 and SMC1A mutations (1) contribute to approximately 5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations.

Three hundred ten individuals with a clinical diagnosis of de Lange syndrome were seen and examined in conjunction with the parent support group. One hundred thirty-four males and 176 females whose ages ranged from birth to 37 years made up the study group. Examination findings were recorded for those features described by de Lange in her original report of the syndrome to determine the frequency and significance of each. In addition, questionnaires were completed by 128 of these families and medical, growth and developmental records were collected. The clinical diagnosis seems best supported by the facial features of the syndrome including the long eyelashes and confluent eyebrows (synophrys), although additional characteristics are needed. Only 27% had the upper limb deficiencies commonly associated with the syndrome. Growth was retarded in nearly all individuals, often of prenatal onset. Medical problems occurred frequently and most often involved the eye and ear, as well as the cardiac and gastrointestinal systems. Of 14 deaths, almost half were secondary to cardiac or gastrointestinal complications. The recurrence risk in 377 sibs of the patients was calculated to be less than 1%. Although development lagged significantly in speech, most individuals developed good self-help skills. The study demonstrated a higher proportion of patients affected mildly with the syndrome than is commonly appreciated. This underscores the importance of early recognition and appropriate medical and developmental support.

Cornelia de Lange syndrome (CdLS), also known as Brachmann-de Lange syndrome, is a well-described multiple malformation syndrome typically involving proportionate small stature, developmental delay, specific facial features, major malformations (particularly the cardiac, gastrointestinal and musculoskeletal systems), and behavioral abnormalities. There is a broad spectrum of clinical involvement, with increasing recognition of a much milder phenotype than previously recognized. Significant progress has been made in recent years in the clinical and molecular delineation of CdLS, necessitating a revision of the diagnostic criteria, more inclusive of the milder cases. In addition, a scoring system of severity has been found to correlate with specific brain changes. Thus, a clinical overview and recommendations for anticipatory guidance are timely in aiding caretakers and professionals to individualize care decisions and maximize developmental potential for individuals with CdLS. These guidelines are derived from consensus based on collective experience of over 500 patients with CdLS, observations of the natural history in children, adolescents, and adults, a review of the literature, and contacts with national support organizations in North America and Europe.