Link: Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome

Link: https://www.ncbi.nlm.nih.gov/pubmed/29330547

Eur J Hum Genet. 2018 Jan 12. doi: 10.1038/s41431-017-0087-x. [Epub ahead of print]
Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome.
Alessandri JL1, Gordon CT2,3, Jacquemont ML4, Gruchy N5, Ajeawung NF6, Benoist G5, Oufadem M2,3, Chebil A7, Duffourd Y8,9, Dumont C10, Gérard M5, Kuentz P8, Jouan T8,9, Filippini F2,3, Nguyen TTM6, Alibeu O3,11, Bole-Feysot C3,11, Nitschké P3,12, Omarjee A10, Ramful D13, Randrianaivo H4, Doray B14, Faivre L8,9, Amiel J2,3,15, Campeau PM6, Thevenon J8,9,16.
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Abstract
Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.