NRP1 – Congenital Heart Disease

High-resolution single nucleotide polymorphism-based microarray analysis of 58 patients with congenital heart disease (CHD) and additional anomalies identified potentially pathogenic heterozygous copy number variants (CNVs) in 12 unrelated probands (20.7%) ranging from 240 Kb to 9.6 Mb that encompass the NRP1 locus, implicating haploinsufficiency in syndromic CHD ([PMID:22010865]). No familial segregation data were reported, and all events were structural gains or losses rather than point mutations.

Endothelial-specific deletion of Nrp1 in mice using Tie2Cre recapitulates key DiGeorge syndrome-like malformations, including impaired pharyngeal organ growth and distorted cardiac outflow tract cushion organization, distinct from Tbx1-driven mechanisms, demonstrating that NRP1 dosage is critical for cardiovascular morphogenesis ([PMID:22396765]).

Despite limited human segregation evidence, concordant animal model data support a dosage-sensitive, autosomal dominant mechanism by which NRP1 contributes to congenital heart defects. Key take-home: NRP1 should be evaluated in CNV-based diagnostic testing for syndromic CHD.

References

• Congenital heart disease • 2011 • Microdeletions and microduplications in patients with congenital heart disease and multiple congenital anomalies. PMID:22010865
• PloS one • 2012 • Endothelial neuropilin disruption in mice causes DiGeorge syndrome-like malformations via mechanisms distinct to those caused by loss of Tbx1. PMID:22396765

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