Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 08 2023
29 08 2023
Historique:
received:
04
12
2022
accepted:
16
08
2023
medline:
31
8
2023
pubmed:
30
8
2023
entrez:
29
8
2023
Statut:
epublish
Résumé
Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved.
Identifiants
pubmed: 37644014
doi: 10.1038/s41467-023-40909-3
pii: 10.1038/s41467-023-40909-3
pmc: PMC10465531
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5269Investigateurs
Afaf I Al-Sagheir
(AI)
Ahmad M Mansour
(AM)
Ali Alawaji
(A)
Amal Aldhilan
(A)
Amal Alhashem
(A)
Amal Alhemidan
(A)
Amira Nabil
(A)
Arif O Khan
(AO)
Aziza Aljohar
(A)
Badr Alsaleem
(B)
Brahim Tabarki
(B)
Charles Marques Lourenco
(CM)
Eissa Faqeih
(E)
Essam AlShail
(E)
Fatima Almesaifri
(F)
Fuad Al Mutairi
(FA)
Hamad Alzaidan
(H)
Heba Morsy
(H)
Hind Alshihry
(H)
Hisham Alkuraya
(H)
Katta Mohan Girisha
(KM)
Khawla Al-Fayez
(K)
Khalid Al-Rubeaan
(K)
Lilia Kraoua
(L)
Maha Alnemer
(M)
Maha Tulbah
(M)
Maha S Zaki
(MS)
Majid Alfadhel
(M)
Mohammed Abouelhoda
(M)
Marjan M Nezarati
(MM)
Mohammad Al-Qattan
(M)
Mohammad Shboul
(M)
Mohammed Abanemai
(M)
Mohammad A Al-Muhaizea
(MA)
Mohammed Al-Owain
(M)
Mohammed Sameer Bafaqeeh
(MS)
Muneera Alshammari
(M)
Musaad Abukhalid
(M)
Nada Alsahan
(N)
Nada Derar
(N)
Neama Meriki
(N)
Saeed A Bohlega
(SA)
Saeed Al Tala
(SA)
Saad Alhassan
(S)
Sami Wali
(S)
Sarar Mohamed
(S)
Serdar Coskun
(S)
Sermin Saadeh
(S)
Tinatin Tkemaladze
(T)
Wesam Kurdi
(W)
Zainab Ahmed Alhumaidi
(ZA)
Zuhair Rahbeeni
(Z)
Informations de copyright
© 2023. Springer Nature Limited.
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