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

Affiliations expand

• PMID: 36322149
• DOI: 10.1016/j.gim.2022.09.007

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.

Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.

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

Affiliations expand

• PMID: 36322149
• DOI: 10.1016/j.gim.2022.09.007

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.

Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.

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

Affiliations expand

• PMID: 36322149
• DOI: 10.1016/j.gim.2022.09.007

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.

Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.