Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India

Calpainopathy is caused by mutations in the CAPN3. There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present...

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Autores principales:	Valakunja H. Ganaraja, Kiran Polavarapu, Mainak Bardhan, Veeramani Preethish-Kumar, Shingavi Leena, Ram M. Anjanappa, Seena Vengalil, Saraswati Nashi, Gautham Arunachal, Swetha Gunasekaran, Dhaarini Mohan, Sanita Raju, Gopikrishnan Unnikrishnan, Akshata Huddar, Valasani Ravi-Kiran, Priya T. Thomas, Atchayaram Nalini
Formato:	article
Lenguaje:	EN
Publicado:	Georg Thieme Verlag KG 2021
Materias:	capn3 muscular dystrophy lgmdr1 next-generation sequencing Genetics QH426-470 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/75ac141fc6ea457c8322411f21a69471
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spelling	oai:doaj.org-article:75ac141fc6ea457c8322411f21a694712021-11-09T23:53:43ZDisease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India2699-940410.1055/s-0041-1736567https://doaj.org/article/75ac141fc6ea457c8322411f21a694712021-11-01T00:00:00Zhttp://www.thieme-connect.de/DOI/DOI?10.1055/s-0041-1736567https://doaj.org/toc/2699-9404Calpainopathy is caused by mutations in the CAPN3. There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.Valakunja H. GanarajaKiran PolavarapuMainak BardhanVeeramani Preethish-KumarShingavi LeenaRam M. AnjanappaSeena VengalilSaraswati NashiGautham ArunachalSwetha GunasekaranDhaarini MohanSanita RajuGopikrishnan UnnikrishnanAkshata HuddarValasani Ravi-KiranPriya T. ThomasAtchayaram NaliniGeorg Thieme Verlag KGarticle capn3 muscular dystrophylgmdr1next-generation sequencingGeneticsQH426-470Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENGlobal Medical Genetics (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	capn3 muscular dystrophy lgmdr1 next-generation sequencing Genetics QH426-470 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	capn3 muscular dystrophy lgmdr1 next-generation sequencing Genetics QH426-470 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Valakunja H. Ganaraja Kiran Polavarapu Mainak Bardhan Veeramani Preethish-Kumar Shingavi Leena Ram M. Anjanappa Seena Vengalil Saraswati Nashi Gautham Arunachal Swetha Gunasekaran Dhaarini Mohan Sanita Raju Gopikrishnan Unnikrishnan Akshata Huddar Valasani Ravi-Kiran Priya T. Thomas Atchayaram Nalini Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India
description	Calpainopathy is caused by mutations in the CAPN3. There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.
format	article
author	Valakunja H. Ganaraja Kiran Polavarapu Mainak Bardhan Veeramani Preethish-Kumar Shingavi Leena Ram M. Anjanappa Seena Vengalil Saraswati Nashi Gautham Arunachal Swetha Gunasekaran Dhaarini Mohan Sanita Raju Gopikrishnan Unnikrishnan Akshata Huddar Valasani Ravi-Kiran Priya T. Thomas Atchayaram Nalini
author_facet	Valakunja H. Ganaraja Kiran Polavarapu Mainak Bardhan Veeramani Preethish-Kumar Shingavi Leena Ram M. Anjanappa Seena Vengalil Saraswati Nashi Gautham Arunachal Swetha Gunasekaran Dhaarini Mohan Sanita Raju Gopikrishnan Unnikrishnan Akshata Huddar Valasani Ravi-Kiran Priya T. Thomas Atchayaram Nalini
author_sort	Valakunja H. Ganaraja
title	Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India
title_short	Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India
title_full	Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India
title_fullStr	Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India
title_full_unstemmed	Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India
title_sort	disease progression and mutation pattern in a large cohort of lgmd r1/lgmd 2a patients from india
publisher	Georg Thieme Verlag KG
publishDate	2021
url	https://doaj.org/article/75ac141fc6ea457c8322411f21a69471
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Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India

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