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Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.

ABSTRACT: Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype.

SUBMITTER: Mannini L

PROVIDER: S-EPMC3880228 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.

Mannini Linda L Cucco Francesco F Quarantotti Valentina V Krantz Ian D ID Musio Antonio A

Human mutation 20130916 12

Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been id ...[more]

PMID: 24038889

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Project description:BackgroundCornelia de Lange (CdLS) is a rare genetic disorder that affects most body systems. Variants in multiple genes including NIPBL and SMC1A, can cause the syndrome. To date, literature on genotype-phenotype associations in individuals with CdLS is extremely limited, although studies suggest some differences in clinical phenotype severity across variants. This study aimed to examine and compare neurobehavioral differences and developmental variability across CdLS genes, specifically NIPBL and SMC1A, and identify genotype-phenotype correlations.Participants and methodsThis patient-reported outcomes study included accessing data from the Coordination of Rare Diseases registry at Sanford. Parents of a total of 26 children/adults with CdLS and a known variant in NIPBL (Mean age = 20.46 years, SD = 11.21) and 12 with a known variant in SMC1A (Mean age = 11.08 years, SD = 9.04) completed a series of questionnaires regarding their child's developmental history. This included attainment of common language and motor milestones, intervention history, and behavior functioning. Developmental history and reported behavior regulation difficulties were compared across variant groups.ResultsOverall, individuals with a pathogenic variant in NIPBL or SMC1A were similarly delayed across motor and language milestones with about 70% not using phrase speech and 30-50% not walking by 5 years of age. However, those with NIPBL variants showed more severity in behavioral phenotype, namely with more repetitive behaviors, tantrums, and withdrawn behaviors. In addition, these individuals were more likely than those with SMC1A variants to demonstrate self-injurious behaviors, and anxiety. Both groups yielded a similar proportion of participants who participated in speech and occupational therapy, however those with SMC1A variants were more likely to engage in physical therapy. Both clinical groups report low rate of communicative or assistive device use despite a large proportion of participants never mastering single word or sentence use.ConclusionsStudy results are consistent with recent investigations highlighting more severe behavioral phenotype, particularly autistic features, anxiety, and behavior regulation challenges, among those with NIPBL variants albeit comparable developmental milestones. Both groups endorsed very elevated attention problems. Findings highlight importance of early interventions, including behavioral health services.

Dataset Information

Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.

Publications

Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome.

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