Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement

Abstract

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.

Fig. 1. Facial phenotype of individuals with Cornelia de Lange syndrome.

a | Classic Cornelia de Lange syndrome (CdLS) phenotype resulting from an NIPBL variant. b | Non-classic CdLS phenotype in an individual harbouring an NIPBL variant. c | Adult with the classic phenotype (NIPBL variant). d | Non-classic phenotype in individual with an SMC1A variant. e | Classic phenotype in an individual with an SMC3 variant. f | Non-classic phenotype in an individual with a RAD21 variant. g | Non-classic phenotype in an individual with an HDAC8 variant. h | Non-classic phenotype in an individual with an ANKRD11 variant.

Fig. 2. The phenotypes classified as Cornelia de Lange syndrome can be defined as a spectrum.

The Cornelia de Lange syndrome (CdLS) spectrum includes individuals with the classic CdLS phenotype in whom a pathogenic variant in a gene involved in cohesin functioning has or has not been identified (if molecular confirmation is absent, the diagnosis can still be determined clinically), as well as individuals with a non-classic CdLS phenotype who harbour a pathogenic variant in a cohesin function-relevant gene. Individuals who carry a presumed pathogenic variant in a cohesin function-relevant gene but exhibit little or no resemblance to the classic CdLS phenotype do not fall within the CdLS spectrum. Please note that mildly affected and severely affected individuals may present both classic and non-classic CdLS. The question mark indicates that there may be genes causing CdLS spectrum that do not have a cohesin function; such genes are unknown at present, but their existence cannot be excluded.

Fig. 3. Cardinal facial features of Cornelia de Lange syndrome.

Facial features that are the most characteristic for Cornelia de Lange syndrome (CdLS) include eye manifestations such as synophrys (meeting of the medial eyebrows in the midline) and thick eyebrows, a short nose, concave nasal ridge and upturned nasal tip, a long and smooth philtrum, a thin upper lip vermilion and downturned corners of the mouth. Non-facial features (not shown) that are considered to be cardinal features of CdLS include hand oligodactyly (the congenital absence of one or more fingers), adactyly (the absence of all fingers and/or toes) and congenital diaphragmatic hernia.

Fig. 4. Cornelia de Lange syndrome is a cohesinopathy.

Cornelia de Lange syndrome (CdLS) is caused by genetic variants that affect subunits or regulators of the cohesin complex. The structural core components double-strand break repair protein rad21 homologue (RAD21), structural maintenance of chromosomes protein 1A (SMC1A) and SMC3 of cohesin are thought to form a tripartite ring entrapping chromatids. In humans, cohesin subunit SA1 (STAG1), STAG2 or STAG3 directly attach to the ring and form part of the core complex. Nipped-B-like protein (NIPBL) and MAU2 chromatid cohesion factor homologue form a heterodimeric complex named kollerin that is required for cohesin loading onto DNA, and in which bromodomain-containing protein 4 (BRD4) interacts with NIPBL. Histone deacetylase 8 (HDAC8) regulates the cohesin complex release from chromatin by deacetylating SMC3. The functional interaction of ankyrin repeat domain-containing protein 11 (ANKRD11) with cohesin is under study but is currently unknown. Ac, acetyl group; AFF4, AF4/FMR2 family member 4; EF, elongation factor; RNAPII, RNA polymerase II; TF, transcription factor.

Fig. 5. Molecular diagnostic pathways for Cornelia de Lange syndrome.

In individuals with the classic Cornelia de Lange syndrome (CdLS) phenotype, the first-line molecular diagnostic approach should be next-generation sequencing (NGS)-based screening — either gene panel, whole-exome sequencing (WES) or whole-genome sequencing (WGS) — including currently known CdLS genes (NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8 and ANKRD11). If NGS is not available, molecular testing should begin with targeted sequencing of NIPBL. In individuals with the non-classic CdLS phenotype, the phenotype itself may allow experienced clinicians to determine which candidate gene should be sequenced first; if this cannot be determined, WES or WGS can be performed. In the case of negative results, NIPBL and subsequently the other CdLS genes should be tested for mosaicism using tissues other than blood, for example, fibroblasts, buccal swabs or bladder epithelial cells from urine. Deletion and duplication testing of NIPBL can be carried out using multiplex ligation-dependent probe amplification (MLPA) or chromosome microarray if first-line testing is not WES or WGS, through which deletions and duplications can be readily detected. If WES or WGS are used for first-line testing, the data can be investigated further for variants in other genes.