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NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.

ABSTRACT: 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.

SUBMITTER: Gillis LA

PROVIDER: S-EPMC1182048 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature

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NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.

Gillis Lynette A LA McCallum Jennifer J Kaur Maninder M DeScipio Cheryl C Yaeger Dinah D Mariani Allison A Kline Antonie D AD Li Hui-hua HH Devoto Marcella M Jackson Laird G LG Krantz Ian D ID

American journal of human genetics 20040818 4

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 ...[more]

PMID: 15318302

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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

NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.

Publications

NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.

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