Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis

Abstract Background Osteopetrosis is characterized by increased bone density and bone marrow cavity stenosis due to a decrease in the number of osteoclasts or the dysfunction of their differentiation and absorption properties usually caused by biallelic variants of the TCIRG1 and CLCN7 genes. Method...

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Autores principales:	Huanhuan Liang, Niu Li, Ru‐en Yao, Tingting Yu, Lixia Ding, Jing Chen, Jian Wang
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	autosomal recessive osteopetrosis cDNA sequencing CLCN7 novel variant TCIRG1 Genetics QH426-470
Acceso en línea:	https://doaj.org/article/b081c2e76e334c6e83a804ab1ec8098b
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spelling	oai:doaj.org-article:b081c2e76e334c6e83a804ab1ec8098b2021-11-21T19:38:53ZClinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis2324-926910.1002/mgg3.1815https://doaj.org/article/b081c2e76e334c6e83a804ab1ec8098b2021-11-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1815https://doaj.org/toc/2324-9269Abstract Background Osteopetrosis is characterized by increased bone density and bone marrow cavity stenosis due to a decrease in the number of osteoclasts or the dysfunction of their differentiation and absorption properties usually caused by biallelic variants of the TCIRG1 and CLCN7 genes. Methods In this study, we describe five Chinese children who presented with anemia, thrombocytopenia, hepatosplenomegaly, repeated infections, and increased bone density. Whole‐exome sequencing identified five compound heterozygous variants of the CLCN7 and TCIRG1 genes in these patients. Results Patient 1 had a novel variant c.1555C>T (p.L519F) and a previously reported pathogenic variant c.2299C>T (p.R767W) in CLCN7. Patient 2 harbored a novel missense variant (c.1025T>C; p.L342P) and a novel splicing variant (c.286‐9G>A) in CLCN7. Patients 3A and 3B from one family displayed the same compound heterozygous TCIRG1 variant, including a novel frameshift variant (c.1370del; p.T457Tfs71) and a novel splicing variant (c.1554+2T>C). In Patient 4, two novel variants were identified in the TCIRG1 gene: c.676G>T; p.E226 and c.1191del; p.P398Sfs5. Patient 5 harbored two known pathogenic variants, c.909C>A (p.Y303) and c.2008C>T (p.R670), in TCIRG1. Analysis of the products obtained from the reverse transcription‐polymerase chain reaction revealed that the c.286‐9G>A variant in CLCN7 of patient 2 leads to intron 3 retention, resulting in the formation of a premature termination codon (p.E95Vfs8). These five patients were eventually diagnosed with autosomal recessive osteopetrosis, and the three children with TCIRG1 variants received hematopoietic stem cell transplantation. Conclusions Our results expand the spectrum of variation of genes related to osteopetrosis and deepen the understanding of the relationship between the genotype and clinical characteristics of osteopetrosis.Huanhuan LiangNiu LiRu‐en YaoTingting YuLixia DingJing ChenJian WangWileyarticleautosomal recessive osteopetrosiscDNA sequencingCLCN7novel variantTCIRG1GeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autosomal recessive osteopetrosis cDNA sequencing CLCN7 novel variant TCIRG1 Genetics QH426-470
spellingShingle	autosomal recessive osteopetrosis cDNA sequencing CLCN7 novel variant TCIRG1 Genetics QH426-470 Huanhuan Liang Niu Li Ru‐en Yao Tingting Yu Lixia Ding Jing Chen Jian Wang Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis
description	Abstract Background Osteopetrosis is characterized by increased bone density and bone marrow cavity stenosis due to a decrease in the number of osteoclasts or the dysfunction of their differentiation and absorption properties usually caused by biallelic variants of the TCIRG1 and CLCN7 genes. Methods In this study, we describe five Chinese children who presented with anemia, thrombocytopenia, hepatosplenomegaly, repeated infections, and increased bone density. Whole‐exome sequencing identified five compound heterozygous variants of the CLCN7 and TCIRG1 genes in these patients. Results Patient 1 had a novel variant c.1555C>T (p.L519F) and a previously reported pathogenic variant c.2299C>T (p.R767W) in CLCN7. Patient 2 harbored a novel missense variant (c.1025T>C; p.L342P) and a novel splicing variant (c.286‐9G>A) in CLCN7. Patients 3A and 3B from one family displayed the same compound heterozygous TCIRG1 variant, including a novel frameshift variant (c.1370del; p.T457Tfs71) and a novel splicing variant (c.1554+2T>C). In Patient 4, two novel variants were identified in the TCIRG1 gene: c.676G>T; p.E226 and c.1191del; p.P398Sfs5. Patient 5 harbored two known pathogenic variants, c.909C>A (p.Y303) and c.2008C>T (p.R670), in TCIRG1. Analysis of the products obtained from the reverse transcription‐polymerase chain reaction revealed that the c.286‐9G>A variant in CLCN7 of patient 2 leads to intron 3 retention, resulting in the formation of a premature termination codon (p.E95Vfs8). These five patients were eventually diagnosed with autosomal recessive osteopetrosis, and the three children with TCIRG1 variants received hematopoietic stem cell transplantation. Conclusions Our results expand the spectrum of variation of genes related to osteopetrosis and deepen the understanding of the relationship between the genotype and clinical characteristics of osteopetrosis.
format	article
author	Huanhuan Liang Niu Li Ru‐en Yao Tingting Yu Lixia Ding Jing Chen Jian Wang
author_facet	Huanhuan Liang Niu Li Ru‐en Yao Tingting Yu Lixia Ding Jing Chen Jian Wang
author_sort	Huanhuan Liang
title	Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis
title_short	Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis
title_full	Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis
title_fullStr	Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis
title_full_unstemmed	Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis
title_sort	clinical and molecular characterization of five chinese patients with autosomal recessive osteopetrosis
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/b081c2e76e334c6e83a804ab1ec8098b
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_version_	1718418720298106880

Clinical and molecular characterization of five Chinese patients with autosomal recessive osteopetrosis

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