Cargando…

Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing

Spinal muscular atrophy, a leading cause of early infant death, is caused by bi-allelic mutations of SMN1. Sequence analysis of SMN1 is challenging due to high sequence similarity with its paralog SMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree informati...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Xiao, Harting, John, Farrow, Emily, Thiffault, Isabelle, Kasperaviciute, Dalia, Hoischen, Alexander, Gilissen, Christian, Pastinen, Tomi, Eberle, Michael A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943720/
https://www.ncbi.nlm.nih.gov/pubmed/36669496
http://dx.doi.org/10.1016/j.ajhg.2023.01.001
_version_ 1784891768034033664
author Chen, Xiao
Harting, John
Farrow, Emily
Thiffault, Isabelle
Kasperaviciute, Dalia
Hoischen, Alexander
Gilissen, Christian
Pastinen, Tomi
Eberle, Michael A.
author_facet Chen, Xiao
Harting, John
Farrow, Emily
Thiffault, Isabelle
Kasperaviciute, Dalia
Hoischen, Alexander
Gilissen, Christian
Pastinen, Tomi
Eberle, Michael A.
author_sort Chen, Xiao
collection PubMed
description Spinal muscular atrophy, a leading cause of early infant death, is caused by bi-allelic mutations of SMN1. Sequence analysis of SMN1 is challenging due to high sequence similarity with its paralog SMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree information, it is currently not possible to identify silent carriers (2+0) with two copies of SMN1 on one chromosome and zero copies on the other. We developed Paraphase, an informatics method that identifies full-length SMN1 and SMN2 haplotypes, determines the gene copy numbers, and calls phased variants using long-read PacBio HiFi data. The SMN1 and SMN2 copy-number calls by Paraphase are highly concordant with orthogonal methods (99.2% for SMN1 and 100% for SMN2). We applied Paraphase to 438 samples across 5 ethnic populations to conduct a population-wide haplotype analysis of these highly homologous genes. We identified major SMN1 and SMN2 haplogroups and characterized their co-segregation through pedigree-based analyses. We identified two SMN1 haplotypes that form a common two-copy SMN1 allele in African populations. Testing positive for these two haplotypes in an individual with two copies of SMN1 gives a silent carrier risk of 88.5%, which is significantly higher than the currently used marker (1.7%–3.0%). Extending beyond simple copy-number testing, Paraphase can detect pathogenic variants and enable potential haplotype-based screening of silent carriers through statistical phasing of haplotypes into alleles. Future analysis of larger population data will allow identification of more diverse haplotypes and genetic markers for silent carriers.
format Online
Article
Text
id pubmed-9943720
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-99437202023-02-23 Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing Chen, Xiao Harting, John Farrow, Emily Thiffault, Isabelle Kasperaviciute, Dalia Hoischen, Alexander Gilissen, Christian Pastinen, Tomi Eberle, Michael A. Am J Hum Genet Article Spinal muscular atrophy, a leading cause of early infant death, is caused by bi-allelic mutations of SMN1. Sequence analysis of SMN1 is challenging due to high sequence similarity with its paralog SMN2. Both genes have variable copy numbers across populations. Furthermore, without pedigree information, it is currently not possible to identify silent carriers (2+0) with two copies of SMN1 on one chromosome and zero copies on the other. We developed Paraphase, an informatics method that identifies full-length SMN1 and SMN2 haplotypes, determines the gene copy numbers, and calls phased variants using long-read PacBio HiFi data. The SMN1 and SMN2 copy-number calls by Paraphase are highly concordant with orthogonal methods (99.2% for SMN1 and 100% for SMN2). We applied Paraphase to 438 samples across 5 ethnic populations to conduct a population-wide haplotype analysis of these highly homologous genes. We identified major SMN1 and SMN2 haplogroups and characterized their co-segregation through pedigree-based analyses. We identified two SMN1 haplotypes that form a common two-copy SMN1 allele in African populations. Testing positive for these two haplotypes in an individual with two copies of SMN1 gives a silent carrier risk of 88.5%, which is significantly higher than the currently used marker (1.7%–3.0%). Extending beyond simple copy-number testing, Paraphase can detect pathogenic variants and enable potential haplotype-based screening of silent carriers through statistical phasing of haplotypes into alleles. Future analysis of larger population data will allow identification of more diverse haplotypes and genetic markers for silent carriers. Elsevier 2023-02-02 2023-01-19 /pmc/articles/PMC9943720/ /pubmed/36669496 http://dx.doi.org/10.1016/j.ajhg.2023.01.001 Text en © 2023 Pacific Biosciences, Inc https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Chen, Xiao
Harting, John
Farrow, Emily
Thiffault, Isabelle
Kasperaviciute, Dalia
Hoischen, Alexander
Gilissen, Christian
Pastinen, Tomi
Eberle, Michael A.
Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
title Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
title_full Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
title_fullStr Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
title_full_unstemmed Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
title_short Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing
title_sort comprehensive smn1 and smn2 profiling for spinal muscular atrophy analysis using long-read pacbio hifi sequencing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943720/
https://www.ncbi.nlm.nih.gov/pubmed/36669496
http://dx.doi.org/10.1016/j.ajhg.2023.01.001
work_keys_str_mv AT chenxiao comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT hartingjohn comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT farrowemily comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT thiffaultisabelle comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT kasperaviciutedalia comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT hoischenalexander comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT gilissenchristian comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT pastinentomi comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing
AT eberlemichaela comprehensivesmn1andsmn2profilingforspinalmuscularatrophyanalysisusinglongreadpacbiohifisequencing