Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing.
PacBio HiFi
bioinformatics
carrier screening
copy number variations
genetic diseases
genomics
homologous genes
long-read sequencing
segmental duplications
spinal muscular atrophy
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 02 2023
02 02 2023
Historique:
received:
28
10
2022
accepted:
20
12
2022
pubmed:
21
1
2023
medline:
8
2
2023
entrez:
20
1
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36669496
pii: S0002-9297(23)00001-0
doi: 10.1016/j.ajhg.2023.01.001
pmc: PMC9943720
pii:
doi:
Substances chimiques
Survival of Motor Neuron 1 Protein
0
SMN1 protein, human
0
SMN2 protein, human
0
Survival of Motor Neuron 2 Protein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
240-250Informations de copyright
Copyright © 2023 Pacific Biosciences, Inc. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests X.C., J.H., and M.A.E. are employees of Pacific Biosciences.
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