학술논문
Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.
Document Type
Article
Author
AlAbdi, Lama; Shamseldin, Hanan E.; Khouj, Ebtissal; Helaby, Rana; Aljamal, Bayan; Alqahtani, Mashael; Almulhim, Aisha; Hamid, Halima; Hashem, Mais O.; Abdulwahab, Firdous; Abouyousef, Omar; Jaafar, Amal; Alshidi, Tarfa; Al-Owain, Mohammed; Alhashem, Amal; Al Tala, Saeed; Khan, Arif O.; Mardawi, Elham; Alkuraya, Hisham; Faqeih, Eissa
Source
Subject
*WHOLE genome sequencing
*EXOMES
*NUCLEOTIDE sequencing
*LETHAL mutations
*GENE expression
*LIFE sciences
*LACTIC acidosis
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Language
ISSN
1756-994X
Abstract
Background: Long-read whole genome sequencing (lrWGS) has the potential to address the technical limitations of exome sequencing in ways not possible by short-read WGS. However, its utility in autosomal recessive Mendelian diseases is largely unknown. Methods: In a cohort of 34 families in which the suspected autosomal recessive diseases remained undiagnosed by exome sequencing, lrWGS was performed on the Pacific Bioscience Sequel IIe platform. Results: Likely causal variants were identified in 13 (38%) of the cohort. These include (1) a homozygous splicing SV in TYMS as a novel candidate gene for lethal neonatal lactic acidosis, (2) a homozygous non-coding SV that we propose impacts STK25 expression and causes a novel neurodevelopmental disorder, (3) a compound heterozygous SV in RP1L1 with complex inheritance pattern in a family with inherited retinal disease, (4) homozygous deep intronic variants in LEMD2 and SNAP91 as novel candidate genes for neurodevelopmental disorders in two families, and (5) a promoter SNV in SLC4A4 causing non-syndromic band keratopathy. Surprisingly, we also encountered causal variants that could have been identified by short-read exome sequencing in 7 families. The latter highlight scenarios that are especially challenging at the interpretation level. Conclusions: Our data highlight the continued need to address the interpretation challenges in parallel with efforts to improve the sequencing technology itself. We propose a path forward for the implementation of lrWGS sequencing in the setting of autosomal recessive diseases in a way that maximizes its utility. [ABSTRACT FROM AUTHOR]