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Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis.

ABSTRACT: Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities (MIM # 618092) is a congenital disorder derived from pathogenic variants of the B-cell leukemia/lymphoma 11B gene (BCL11B). Several variants have been reported to date. Here, through comprehensive genomic analysis, a novel BCL11B truncation variant, NM_138576.4(BCL11B_v001): c.2439_2452dup [p.(His818Argfs*31)], was identified in a Japanese male patient with developmental delay, distinctive features, and early craniosynostosis.

SUBMITTER: Eto K

PROVIDER: S-EPMC9722650 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis.

Eto Kaoru K Machida Osamu O Yanagishita Tomoe T Shimojima Yamamoto Keiko K Chiba Kentaro K Aihara Yasuo Y Hasegawa Yuuki Y Nagata Miho M Ishihara Yasuki Y Miyashita Yohei Y Asano Yoshihiro Y Nagata Satoru S Yamamoto Toshiyuki T

Human genome variation 20221205 1

Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities (MIM # 618092) is a congenital disorder derived from pathogenic variants of the B-cell leukemia/lymphoma 11B gene (BCL11B). Several variants have been reported to date. Here, through comprehensive genomic analysis, a novel BCL11B truncation variant, NM_138576.4(BCL11B_v001): c.2439_2452dup [p.(His818Argfs*31)], was identified in a Japanese male patient with developmental delay, distinctive features ...[more]

PMID: 36470856

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Project description:BackgroundDevelopmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B.MethodsIn the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)-based mRNA expression were checked using standard methods.ResultsData analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient.ConclusionOur finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis.

Dataset Information

Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis.

Publications

Novel BCL11B truncation variant in a patient with developmental delay, distinctive features, and early craniosynostosis.

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