Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
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Loong Lucy, Tardivo Agostina, Knaus Alexej, Hashim Mona, Pagnamenta Alistair T, Alt Kerstin, Böhrer-Rabel Helena, Caro-Llopis Alfonso, Cole Trevor, Distelmaier Felix, Edery Patrick, Ferreira Carlos R, Jezela-Stanek Aleksandra, Kerr Bronwyn, Kluger Gerhard, Krawitz Peter M, Kuhn Marius, Lemke Johannes R, Lesca Gaetan, Lynch Sally Ann, Martinez Francisco, Maxton Caroline, Mierzewska Hanna, Monfort Sandra, Nicolai Joost, Orellana Carmen, Pal Deb K, Płoski Rafał, Quarrell Oliver W, Rosello Monica, Rydzanicz Małgorzata, Sabir Ataf, Śmigiel Robert, Stegmann Alexander P A, Stewart Helen, Stumpel Constance, Szczepanik Elżbieta, Tzschach Andreas, Wolfe Lynne, Taylor Jenny C, Murakami Yoshiko, Kinoshita Taroh, Bayat Allan, Kini Usha
Аннотация
METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).
RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.
CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.