cDNA sequencing increases the molecular diagnostic yield in Chediak-Higashi syndrome

Author:

Kuptanon Chulaluk,Morimoto Marie,Nicoli Elena-Raluca,Stephen Joshi,Yarnell David S.,Dorward Heidi,Owen William,Parikh Suhag,Ozbek Namik Yasar,Malbora Baris,Ciccone Carla,Gunay-Aygun Meral,Gahl William A.,Introne Wendy J.,Malicdan May Christine V.

Abstract

Introduction: Chediak-Higashi syndrome (CHS) is rare autosomal recessive disorder caused by bi-allelic variants in the Lysosomal Trafficking Regulator (LYST) gene. Diagnosis is established by the detection of pathogenic variants in LYST in combination with clinical evidence of disease. Conventional molecular genetic testing of LYST by genomic DNA (gDNA) Sanger sequencing detects the majority of pathogenic variants, but some remain undetected for several individuals clinically diagnosed with CHS. In this study, cDNA Sanger sequencing was pursued as a complementary method to identify variant alleles that are undetected by gDNA Sanger sequencing and to increase molecular diagnostic yield.Methods: Six unrelated individuals with CHS were clinically evaluated and included in this study. gDNA Sanger sequencing and cDNA Sanger sequencing were performed to identify pathogenic LYST variants.Results: Ten novel LYST alleles were identified, including eight nonsense or frameshift variants and two in-frame deletions. Six of these were identified by conventional gDNA Sanger sequencing; cDNA Sanger sequencing was required to identify the remaining variant alleles.Conclusion: By utilizing cDNA sequencing as a complementary technique to identify LYST variants, a complete molecular diagnosis was obtained for all six CHS patients. In this small CHS cohort, the molecular diagnostic yield was increased, and canonical splice site variants identified from gDNA Sanger sequencing were validated by cDNA sequencing. The identification of novel LYST alleles will aid in diagnosing patients and these molecular diagnoses will also lead to genetic counseling, access to services and treatments and clinical trials in the future.

Publisher

Frontiers Media SA

Subject

Genetics (clinical),Genetics,Molecular Medicine

Reference31 articles.

1. Identification of the homologous beige and Chediak-Higashi syndrome genes;Barbosa;Nature,1996

2. Neutropenia crónica maligna familiar con granulaciones atípicas de los leucocitos;Béguez César;Bol. Soc. Cuba. Pediatr.,1943

3. Chediak-Higashi syndrome presenting as young-onset levodopa-responsive parkinsonism;Bhambhani;Mov. Disord.,2013

4. Case report: Partial uniparental disomy unmasks a novel recessive mutation in the LYST gene in a patient with a severe phenotype of Chediak-Higashi syndrome;Boluda-Navarro;Front. Immunol.,2021

5. Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak-Higashi syndrome;Certain;Blood,2000

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3