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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Genetics in Medicine |
| Vol/bind | 25 |
| Udgave nummer | 1 |
| Sider (fra-til) | 37-48 |
| Antal sider | 12 |
| ISSN | 1098-3600 |
| DOI | |
| Status | Udgivet - jan. 2023 |
| Udgivet eksternt | Ja |
Bibliografisk note
Funding Information:This research was supported by the NIHR Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford . The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003]. This study makes use of DECIPHER ( https://www.deciphergenomics.org ), which is funded by Wellcome . See Nature PMID: 25533962 or www.ddduk.org/access.html for full acknowledgment. Part of this work was generated within ITHACA: European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability. Part of this work was supported by the Intramural Research Program of the National Human Genome Research Institute (C.R.F. and L.W.). L.L. received funding from the NIHR Greenshoots Scheme. U.K., J.C.T., and A.T.P. are funded by the NIHR Oxford Biomedical Research Centre .
Funding Information:
This research was supported by the NIHR Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford. The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003]. This study makes use of DECIPHER (https://www.deciphergenomics.org), which is funded by Wellcome. See Nature PMID: 25533962 or www.ddduk.org/access.html for full acknowledgment. Part of this work was generated within ITHACA: European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability. Part of this work was supported by the Intramural Research Program of the National Human Genome Research Institute (C.R.F. and L.W.). L.L. received funding from the NIHR Greenshoots Scheme. U.K. J.C.T. and A.T.P. are funded by the NIHR Oxford Biomedical Research Centre.
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