NIPBL – Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS; MONDO:0016033) is an autosomal dominant developmental disorder characterized by distinctive craniofacial dysmorphism, growth retardation, limb reduction anomalies and cognitive impairment. Heterozygous mutations in NIPBL (HGNC:28862), encoding the cohesin‐loader delangin, underlie approximately 60–70% of CdLS cases due to haploinsufficiency and resulting dosage‐sensitive cohesin defects ([PMID:15146186]). The estimated prevalence of CdLS is ~1 in 10,000 live births.

1 Clinical Validity

On the basis of over 199 unique NIPBL mutations identified in 246 unrelated CdLS patients over >15 years with recurrent de novo and familial transmission, consistent segregation, and functional concordance, the NIPBL–CdLS association meets ClinGen criteria for a Definitive gene–disease relationship (Definitive; multiple independent cohorts; functional assays concordant) ([PMID:20824775]).

2 Genetic Evidence

Inheritance is autosomal dominant with the majority of NIPBL variants arising de novo. Segregation has been documented in at least 4 affected relatives across multiple families, including father-to-daughter and mother-to-sibling transmission of promoter and coding mutations ([PMID:16799922]). Over 246 probands harbor heterozygous NIPBL variants, of which ~70% are loss-of-function (nonsense, frameshift, essential splice) and ~25% missense; deep intronic and 5′-UTR mutations are also observed ([PMID:20824775]). A representative frameshift allele is c.2827delA (p.Ser943ValfsTer11) identified in both germline and mosaic contexts (PMID:20331678).

3 Functional Evidence

NIPBL haploinsufficiency disrupts cohesin loading and chromatin regulation through multiple mechanisms. The NIPBL N-terminus recruits histone deacetylases 1 and 3, and promotes local chromatin modification and transcriptional repression, effects abrogated by patient missense alleles ([PMID:18854353]). Moreover, NIPBL directly interacts with MAU2 to mediate cohesin loading; missense mutations in this interface reduce MAU2 binding and cohesin deposition on DNA ([PMID:21934712]). These cellular assays concord with the human CdLS phenotype.

4 Conflicting Evidence

No substantive conflicting evidence has been reported for NIPBL in CdLS; other cohesinopathies (SMC1A, SMC3, HDAC8, RAD21) produce overlapping but generally milder phenotypes.

5 Conclusions and Clinical Utility

Collectively, >246 independent NIPBL variants with consistent genotype‐phenotype correlations and mechanistic validation by cohesin‐loading and chromatin assays establish a definitive association between NIPBL haploinsufficiency and Cornelia de Lange syndrome. NIPBL genetic testing is recommended in all patients with suggestive CdLS features to confirm diagnosis, enable recurrence counselling, and inform management.

Key take-home: Heterozygous loss‐of‐function mutations in NIPBL cause multisystem CdLS via haploinsufficiency of cohesin loading, and targeted testing is essential for accurate diagnosis and family planning.

References

• Nature Genetics • 2004 • Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. PMID:15146186
• Human Mutation • 2006 • Father-to-daughter transmission of Cornelia de Lange syndrome caused by a mutation in the 5' untranslated region of the NIPBL Gene. PMID:16799922
• Human Mutation • 2010 • Development of NIPBL locus-specific database using LOVD: from novel mutations to further genotype-phenotype correlations in Cornelia de Lange Syndrome. PMID:20824775
• Nucleic Acids Research • 2008 • The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications. PMID:18854353
• European Journal of Human Genetics • 2012 • Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction. PMID:21934712

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