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

Jean-Luc Alessandri (1) , Christopher T Gordon (2) , Marie-Line Jacquemont (3) , Nicolas Gruchy (4, 5) , Norbert Ajeawung (6) , Guillaume Benoist (4) , Myriam Oufadem (2) , Asma Chebil (7) , Yannis Duffourd (8, 9, 10) , Coralie Dumont (11) , Marion Gérard (4) , Paul Kuentz (9) , Thibaud Jouan (9) , Francesca Filippini (12) , Thi Tuyet Mai Nguyen (6) , Olivier Alibeu (12) , Christine Bole-Feysot (13) , Patrick Nitschke (14) , Asma Omarjee (11) , Duksha Ramful (11) , Hanitra Randrianaivo (11) , Bérénice Doray (15) , Laurence Faivre (9) , Jeanne Amiel (16) , Philippe Campeau (17) , Julien Thévenon (18)

1 Service de réanimation néonatologique et pédiatrique [La Réunion]
2 Equipe Inserm U1163 - Embryology and genetics of human malformation
3 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
4 Service de Génétique [CHU Caen]
5 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
6 Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
7 Pôle Gynécologie Obstétrique [CHM, Mayotte]
8 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
9 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
10 Hôpital d'Enfants [CHU Dijon]
11 Pôle Femme-Mère-Enfant [CHU La Réunion, Saint-Pierre, La Réunion]
12 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
13 Plateforme de génomique [SFR Necker]
14 BIP-D - Plate Forme Paris Descartes de Bioinformatique
15 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
16 Hôpital Necker - Enfants Malades [AP-HP]
17 CHU Sainte Justine [Montréal]
18 Biologie moléculaire et cellulaire de la différenciation

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.

Domaines: Génétique; Génétique humaine; Cancer

Jean-Luc Alessandri, Christopher T Gordon, Marie-Line Jacquemont, Nicolas Gruchy, Norbert Ajeawung, et al.. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome. European Journal of Human Genetics, 2018, 26 (3), pp.340-349. ⟨10.1038/s41431-017-0087-x⟩. ⟨hal-02392961⟩