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Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees

BACKGROUND: Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and benefit gene therapy, and therefore should be recommended for RP patients. This report reveals...

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Autores principales: Chen, Xue, Sheng, Xunlun, Liu, Yani, Li, Zili, Sun, Xiantao, Jiang, Chao, Qi, Rui, Yuan, Shiqin, Wang, Xuhui, Zhou, Ge, Zhen, Yanyan, Xie, Ping, Liu, Qinghuai, Yan, Biao, Zhao, Chen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975579/
https://www.ncbi.nlm.nih.gov/pubmed/29843741
http://dx.doi.org/10.1186/s12967-018-1522-7
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author Chen, Xue
Sheng, Xunlun
Liu, Yani
Li, Zili
Sun, Xiantao
Jiang, Chao
Qi, Rui
Yuan, Shiqin
Wang, Xuhui
Zhou, Ge
Zhen, Yanyan
Xie, Ping
Liu, Qinghuai
Yan, Biao
Zhao, Chen
author_facet Chen, Xue
Sheng, Xunlun
Liu, Yani
Li, Zili
Sun, Xiantao
Jiang, Chao
Qi, Rui
Yuan, Shiqin
Wang, Xuhui
Zhou, Ge
Zhen, Yanyan
Xie, Ping
Liu, Qinghuai
Yan, Biao
Zhao, Chen
author_sort Chen, Xue
collection PubMed
description BACKGROUND: Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and benefit gene therapy, and therefore should be recommended for RP patients. This report reveals the disease causing mutations in two RP pedigrees with confusing inheritance patterns using whole exome sequencing (WES). METHODS: Twenty-five participants including eight patients from two families were recruited and received comprehensive ophthalmic evaluations. WES was applied for mutation identification. Bioinformatics annotations, intrafamilial co-segregation tests, and in silico analyses were subsequently conducted for mutation verification. RESULTS: All patients were clinically diagnosed with RP. The first family included two siblings born to parents with consanguineous marriage; however, no potential pathogenic variant was found shared by both patients. Further analysis revealed that the female patient carried a recurrent homozygous C8ORF37 p.W185*, while the male patient had hemizygous OFD1 p.T120A. The second family was found to segregate mutations in two genes, TULP1 and RP1. Two patients born to consanguineous marriage carried homozygous TULP1 p.R419W, while a recurrent heterozygous RP1 p.L762Yfs*17 was found in another four patients presenting an autosomal dominant inheritance pattern. Crystal structural analysis further indicated that the substitution from arginine to tryptophan at the highly conserved residue 419 of TULP1 could lead to the elimination of two hydrogen bonds between residue 419 and residues V488 and S534. All four genes, including C8ORF37, OFD1, TULP1 and RP1, have been previously implicated in RP etiology. CONCLUSIONS: Our study demonstrates the coexistence of diverse inheritance modes and mutations affecting distinct disease causing genes in two RP families with consanguineous marriage. Our data provide novel insights into assessments of complicated pedigrees, reinforce the genetic complexity of RP, and highlight the need for extensive molecular evaluations in such challenging families with diverse inheritance modes and mutations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1522-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-59755792018-05-31 Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees Chen, Xue Sheng, Xunlun Liu, Yani Li, Zili Sun, Xiantao Jiang, Chao Qi, Rui Yuan, Shiqin Wang, Xuhui Zhou, Ge Zhen, Yanyan Xie, Ping Liu, Qinghuai Yan, Biao Zhao, Chen J Transl Med Research BACKGROUND: Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and benefit gene therapy, and therefore should be recommended for RP patients. This report reveals the disease causing mutations in two RP pedigrees with confusing inheritance patterns using whole exome sequencing (WES). METHODS: Twenty-five participants including eight patients from two families were recruited and received comprehensive ophthalmic evaluations. WES was applied for mutation identification. Bioinformatics annotations, intrafamilial co-segregation tests, and in silico analyses were subsequently conducted for mutation verification. RESULTS: All patients were clinically diagnosed with RP. The first family included two siblings born to parents with consanguineous marriage; however, no potential pathogenic variant was found shared by both patients. Further analysis revealed that the female patient carried a recurrent homozygous C8ORF37 p.W185*, while the male patient had hemizygous OFD1 p.T120A. The second family was found to segregate mutations in two genes, TULP1 and RP1. Two patients born to consanguineous marriage carried homozygous TULP1 p.R419W, while a recurrent heterozygous RP1 p.L762Yfs*17 was found in another four patients presenting an autosomal dominant inheritance pattern. Crystal structural analysis further indicated that the substitution from arginine to tryptophan at the highly conserved residue 419 of TULP1 could lead to the elimination of two hydrogen bonds between residue 419 and residues V488 and S534. All four genes, including C8ORF37, OFD1, TULP1 and RP1, have been previously implicated in RP etiology. CONCLUSIONS: Our study demonstrates the coexistence of diverse inheritance modes and mutations affecting distinct disease causing genes in two RP families with consanguineous marriage. Our data provide novel insights into assessments of complicated pedigrees, reinforce the genetic complexity of RP, and highlight the need for extensive molecular evaluations in such challenging families with diverse inheritance modes and mutations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-018-1522-7) contains supplementary material, which is available to authorized users. BioMed Central 2018-05-29 /pmc/articles/PMC5975579/ /pubmed/29843741 http://dx.doi.org/10.1186/s12967-018-1522-7 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Chen, Xue
Sheng, Xunlun
Liu, Yani
Li, Zili
Sun, Xiantao
Jiang, Chao
Qi, Rui
Yuan, Shiqin
Wang, Xuhui
Zhou, Ge
Zhen, Yanyan
Xie, Ping
Liu, Qinghuai
Yan, Biao
Zhao, Chen
Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees
title Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees
title_full Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees
title_fullStr Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees
title_full_unstemmed Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees
title_short Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees
title_sort distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975579/
https://www.ncbi.nlm.nih.gov/pubmed/29843741
http://dx.doi.org/10.1186/s12967-018-1522-7
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