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Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome

Cornelia de Lange syndrome (CdLS) is an autosomal dominant or X-linked genetic disease with significant genetic heterogeneity. Variants of the NIPBL gene are responsible for CdLS in 60% of patients. Herein, we report the case of a patient with CdLS showing distinctive facial features, microcephaly,...

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Autores principales: Shi, Meizhen, Liang, Yuying, Xie, Bobo, Wei, Xianda, Zheng, Haiyang, Gui, Chunrong, Huang, Rong, Fan, Xin, Li, Chuan, Wei, Xiaojiao, Ma, Yunting, Chen, Shaoke, Chen, Yujun, Gui, Baoheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9726764/
https://www.ncbi.nlm.nih.gov/pubmed/36506332
http://dx.doi.org/10.3389/fgene.2022.1056127
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author Shi, Meizhen
Liang, Yuying
Xie, Bobo
Wei, Xianda
Zheng, Haiyang
Gui, Chunrong
Huang, Rong
Fan, Xin
Li, Chuan
Wei, Xiaojiao
Ma, Yunting
Chen, Shaoke
Chen, Yujun
Gui, Baoheng
author_facet Shi, Meizhen
Liang, Yuying
Xie, Bobo
Wei, Xianda
Zheng, Haiyang
Gui, Chunrong
Huang, Rong
Fan, Xin
Li, Chuan
Wei, Xiaojiao
Ma, Yunting
Chen, Shaoke
Chen, Yujun
Gui, Baoheng
author_sort Shi, Meizhen
collection PubMed
description Cornelia de Lange syndrome (CdLS) is an autosomal dominant or X-linked genetic disease with significant genetic heterogeneity. Variants of the NIPBL gene are responsible for CdLS in 60% of patients. Herein, we report the case of a patient with CdLS showing distinctive facial features, microcephaly, developmental delay, and growth retardation. Whole exome sequencing was performed for the patient, and a novel de novo heterozygous synonymous variant was identified in the deep region of exon 40 in the NIPBL gene (NM_133433.4: c. 6819G > T, p. Gly2273 = ). The clinical significance of the variant was uncertain according to the ACMG/AMP guidelines; however, based on in silico analysis, it was predicted to alter mRNA splicing. To validate the prediction, a reverse transcriptase-polymerase chain reaction was conducted. The variant activated a cryptic splice donor, generating a short transcript of NIPBL. A loss of 137 bp at the 3′ end of NIPBL exon 40 was detected, which potentially altered the open reading frame by inserting multiple premature termination codons. Quantitative real-time PCR analysis showed that the ratio of the transcription level of the full-length transcript to that of the altered short transcript in the patient was 5:1, instead of 1:1. These findings may explain the relatively mild phenotype of the patient, regardless of the loss of function of the truncated protein due to a frameshift in the mRNA. To the best of our knowledge, this study is the first to report a synonymous variant in the deep exon regions of the NIPBL gene responsible for CdLS. The identified variant expands the mutational spectrum of the NIPBL gene. Furthermore, synonymous variations may be pathogenic, which should not be ignored in the clinical and genetic diagnosis of the disease.
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spelling pubmed-97267642022-12-08 Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome Shi, Meizhen Liang, Yuying Xie, Bobo Wei, Xianda Zheng, Haiyang Gui, Chunrong Huang, Rong Fan, Xin Li, Chuan Wei, Xiaojiao Ma, Yunting Chen, Shaoke Chen, Yujun Gui, Baoheng Front Genet Genetics Cornelia de Lange syndrome (CdLS) is an autosomal dominant or X-linked genetic disease with significant genetic heterogeneity. Variants of the NIPBL gene are responsible for CdLS in 60% of patients. Herein, we report the case of a patient with CdLS showing distinctive facial features, microcephaly, developmental delay, and growth retardation. Whole exome sequencing was performed for the patient, and a novel de novo heterozygous synonymous variant was identified in the deep region of exon 40 in the NIPBL gene (NM_133433.4: c. 6819G > T, p. Gly2273 = ). The clinical significance of the variant was uncertain according to the ACMG/AMP guidelines; however, based on in silico analysis, it was predicted to alter mRNA splicing. To validate the prediction, a reverse transcriptase-polymerase chain reaction was conducted. The variant activated a cryptic splice donor, generating a short transcript of NIPBL. A loss of 137 bp at the 3′ end of NIPBL exon 40 was detected, which potentially altered the open reading frame by inserting multiple premature termination codons. Quantitative real-time PCR analysis showed that the ratio of the transcription level of the full-length transcript to that of the altered short transcript in the patient was 5:1, instead of 1:1. These findings may explain the relatively mild phenotype of the patient, regardless of the loss of function of the truncated protein due to a frameshift in the mRNA. To the best of our knowledge, this study is the first to report a synonymous variant in the deep exon regions of the NIPBL gene responsible for CdLS. The identified variant expands the mutational spectrum of the NIPBL gene. Furthermore, synonymous variations may be pathogenic, which should not be ignored in the clinical and genetic diagnosis of the disease. Frontiers Media S.A. 2022-11-23 /pmc/articles/PMC9726764/ /pubmed/36506332 http://dx.doi.org/10.3389/fgene.2022.1056127 Text en Copyright © 2022 Shi, Liang, Xie, Wei, Zheng, Gui, Huang, Fan, Li, Wei, Ma, Chen, Chen and Gui. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Shi, Meizhen
Liang, Yuying
Xie, Bobo
Wei, Xianda
Zheng, Haiyang
Gui, Chunrong
Huang, Rong
Fan, Xin
Li, Chuan
Wei, Xiaojiao
Ma, Yunting
Chen, Shaoke
Chen, Yujun
Gui, Baoheng
Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome
title Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome
title_full Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome
title_fullStr Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome
title_full_unstemmed Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome
title_short Case report: A novel heterozygous synonymous variant in deep exon region of NIPBL gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome
title_sort case report: a novel heterozygous synonymous variant in deep exon region of nipbl gene generating a non-canonical splice donor in a patient with cornelia de lange syndrome
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9726764/
https://www.ncbi.nlm.nih.gov/pubmed/36506332
http://dx.doi.org/10.3389/fgene.2022.1056127
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