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Research: 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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Research: Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study

Genet Med

. 2022 Nov 2;S1098-3600(22)00945-5.

 doi: 10.1016/j.gim.2022.09.007. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/36322149/

Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study

Lucy Loong 1Agostina Tardivo 2Alexej Knaus 3Mona Hashim 4Alistair T Pagnamenta 4Kerstin Alt 5Helena Böhrer-Rabel 5Alfonso Caro-Llopis 6Trevor Cole 7Felix Distelmaier 8Patrick Edery 9Carlos R Ferreira 10Aleksandra Jezela-Stanek 11Bronwyn Kerr 12Gerhard Kluger 5Peter M Krawitz 3Marius Kuhn 5Johannes R Lemke 13Gaetan Lesca 9Sally Ann Lynch 14Francisco Martinez 6Caroline Maxton 15Hanna Mierzewska 16Sandra Monfort 6Joost Nicolai 17Carmen Orellana 6Deb K Pal 18Rafał Płoski 19Oliver W Quarrell 20Monica Rosello 6Małgorzata Rydzanicz 19Ataf Sabir 7Robert Śmigiel 21Alexander P A Stegmann 22Helen Stewart 1Constance Stumpel 22Elżbieta Szczepanik 16Andreas Tzschach 23Lynne Wolfe 10Jenny C Taylor 4Yoshiko Murakami 24Taroh Kinoshita 24Allan Bayat 25Usha Kini 26

Affiliations expand

Abstract

Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.

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.

Keywords: Epilepsy; Fryns syndrome; GPI deficiency; MCAHS1; PIGN.

Genet Med

. 2022 Nov 2;S1098-3600(22)00945-5.

 doi: 10.1016/j.gim.2022.09.007. Online ahead of print.

Genet Med

. 2022 Nov 2;S1098-3600(22)00945-5.

 doi: 10.1016/j.gim.2022.09.007. Online ahead of print.

Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study

Lucy Loong 1Agostina Tardivo 2Alexej Knaus 3Mona Hashim 4Alistair T Pagnamenta 4Kerstin Alt 5Helena Böhrer-Rabel 5Alfonso Caro-Llopis 6Trevor Cole 7Felix Distelmaier 8Patrick Edery 9Carlos R Ferreira 10Aleksandra Jezela-Stanek 11Bronwyn Kerr 12Gerhard Kluger 5Peter M Krawitz 3Marius Kuhn 5Johannes R Lemke 13Gaetan Lesca 9Sally Ann Lynch 14Francisco Martinez 6Caroline Maxton 15Hanna Mierzewska 16Sandra Monfort 6Joost Nicolai 17Carmen Orellana 6Deb K Pal 18Rafał Płoski 19Oliver W Quarrell 20Monica Rosello 6Małgorzata Rydzanicz 19Ataf Sabir 7Robert Śmigiel 21Alexander P A Stegmann 22Helen Stewart 1Constance Stumpel 22Elżbieta Szczepanik 16Andreas Tzschach 23Lynne Wolfe 10Jenny C Taylor 4Yoshiko Murakami 24Taroh Kinoshita 24Allan Bayat 25Usha Kini 26

Affiliations expand

Abstract

Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.

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.

Keywords: Epilepsy; Fryns syndrome; GPI deficiency; MCAHS1; PIGN.

Lucy Loong 1Agostina Tardivo 2Alexej Knaus 3Mona Hashim 4Alistair T Pagnamenta 4Kerstin Alt 5Helena Böhrer-Rabel 5Alfonso Caro-Llopis 6Trevor Cole 7Felix Distelmaier 8Patrick Edery 9Carlos R Ferreira 10Aleksandra Jezela-Stanek 11Bronwyn Kerr 12Gerhard Kluger 5Peter M Krawitz 3Marius Kuhn 5Johannes R Lemke 13Gaetan Lesca 9Sally Ann Lynch 14Francisco Martinez 6Caroline Maxton 15Hanna Mierzewska 16Sandra Monfort 6Joost Nicolai 17Carmen Orellana 6Deb K Pal 18Rafał Płoski 19Oliver W Quarrell 20Monica Rosello 6Małgorzata Rydzanicz 19Ataf Sabir 7Robert Śmigiel 21Alexander P A Stegmann 22Helen Stewart 1Constance Stumpel 22Elżbieta Szczepanik 16Andreas Tzschach 23Lynne Wolfe 10Jenny C Taylor 4Yoshiko Murakami 24Taroh Kinoshita 24Allan Bayat 25Usha Kini 26

Affiliations expand

Abstract

Purpose: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.

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.

Keywords: Epilepsy; Fryns syndrome; GPI deficiency; MCAHS1; PIGN.

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