B Homozygous NRP1 truncating variant in a multiplex family with conotruncal heart defects, lymphatic malformations and genitourinary anomalies

Altunoğlu U., Kaya M., Kalaycı T., Uyguner Z. O.

European Human Genetics Conference, Glasgow, İngiltere, 10 - 13 Haziran 2023, cilt.31, ss.524

  • Yayın Türü: Bildiri / Özet Bildiri
  • Cilt numarası: 31
  • Basıldığı Şehir: Glasgow
  • Basıldığı Ülke: İngiltere
  • Sayfa Sayıları: ss.524
  • İstanbul Üniversitesi Adresli: Evet

Özet

Background/Objectives: Neuropilins (NRP1 and NRP2) are cell surface proteins conserved across species, acting as coreceptors for signal proteins including members of semaphorin and VEGF families. They participate in a multitude of processes: development of the cardiovascular system, (lymph)angiogenesis, neuronal patterning and immune function. NRP1 deficient mice display embryonic lethality due to a severely abnormal cardiovascular phenotype, resembling those of Vegf and Vefgr2 knockouts. Shaheen et al. (2015) reported a homozygous null mutation in the proband of a multiplex family with truncus arteriosus. Methods: Exome sequencing in the proband was performed in a consanguineous multiplex family with conotruncal anomalies. Affected and unaffected family members were screened for the candidate variant to reveal segregation. Results: We present a 32-day-old girl born to 1st cousins onceremoved, with a severe congenital heart defect comprising atrial and ventricular septal defects with patent ductus arteriosus, left microphthalmia with cystic lymphatic malformation, and renal anomalies. Weight was 3500 g (14p), height 52.5 cm (31p) and head circumference 37 cm (46p). Cranial MRI was unremarkable. The parents had a medical abortion due to a huge parapharyngeal lympangioma, and two children deceased due to severe coarctation of the aorta and tetralogy of Fallot, respectively. Chromosomal array was normal. WES revealed homozygous nonsense c.1213C>T; p.(Arg405*) in NRP1 [NM_003873], segregating with the phenotype in unaffected parents and sister, and one deceased affected sibling. Parental echocardiograms were normal. Conclusion: This is the second report of a family with homozygous truncating variants in NRP1, further supporting NRP1 as a human disease gene. References: https://doi.org/10.1016/s0092-8674(00)80534-6, https://doi.org/10.1016/s0092-8674(00)81402-6, https://doi.org/ 10.1073/pnas.022017899, https://doi.org/10.1136/jmedgenet2015-102992. Grants: None. Conflict of Interest: None declared.