Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly
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| Titel: | Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly |
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| Autoren: | Eyyup Uctepe, Barbara Vona, Fatma Nisa Esen, F. Mujgan Sonmez, Thomas Smol, Sait Tümer, Hanifenur Mancılar, Dilan Ece Geylan Durgun, Odile Boute, Meysam Moghbeli, Ehsan Ghayoor Karimiani, Narges Hashemi, Behnoosh Bakhshoodeh, Hyung Goo Kim, Reza Maroofian, Ahmet Yesilyurt |
| Weitere Verfasser: | Uctepe, Eyyup, Vona, Barbara, Esen, Fatma Nisa, Sonmez, F. Mujgan, Smol, Thomas, Tümer, Sait, Mancılar, Hanifenur, Geylan Durgun, Dilan Ece, Boute, Odile, Moghbeli, Meysam, Yesilyurt, Ahmet, Université de Lille, LillOA |
| Quelle: | Eur J Hum Genet |
| Verlagsinformationen: | Springer Science and Business Media LLC, 2023. |
| Publikationsjahr: | 2023 |
| Schlagwörter: | [SDV] Life Sciences [q-bio], Cysteine Endopeptidases, Phenotype, 38/22, 38/77, 59/57, 631/208/2489/1512, 45/47, Lissencephaly/diagnostic imaging [MeSH], 631/208/2489/144, Codon, Nonsense [MeSH], Neurodevelopmental Disorders/genetics [MeSH], 38/109, 45/22, Phenotype [MeSH], 42/44, Cysteine Endopeptidases/genetics [MeSH], 692/308/2056, Humans [MeSH], Caspase 2/genetics [MeSH], Lissencephaly/genetics [MeSH], 38/44, 692/699/375/366, Article, 45/23, Alleles [MeSH], 692/420/2489/144, article, Neurodevelopmental Disorders, Codon, Nonsense, Caspase 2, Humans, Lissencephaly, Alleles |
| Beschreibung: | Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1476-5438 1018-4813 |
| DOI: | 10.1038/s41431-023-01461-2 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/37880421 https://resolver.sub.uni-goettingen.de/purl?gro-2/138772 https://repository.publisso.de/resource/frl:6522717 https://hal.univ-lille.fr/hal-04630949v1 https://hal.univ-lille.fr/hal-04630949v1/document https://doi.org/10.1038/s41431-023-01461-2 https://discovery-pp.ucl.ac.uk/id/eprint/10180733/ |
| Rights: | CC BY |
| Dokumentencode: | edsair.doi.dedup.....579e9862fa1a870a97c63510dc2d4d40 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function. |
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| ISSN: | 14765438 10184813 |
| DOI: | 10.1038/s41431-023-01461-2 |