Ontology highlight
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.
SUBMITTER: AlAbdi L
PROVIDER: S-EPMC10720148 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
AlAbdi Lama L Shamseldin Hanan E HE Khouj Ebtissal E Helaby Rana R Aljamal Bayan B Alqahtani Mashael M Almulhim Aisha A Hamid Halima H Hashem Mais O MO Abdulwahab Firdous F Abouyousef Omar O Jaafar Amal A Alshidi Tarfa T Al-Owain Mohammed M Alhashem Amal A Al Tala Saeed S Khan Arif O AO Mardawi Elham E Alkuraya Hisham H Faqeih Eissa E Afqi Manal M Alkhalifi Salwa S Rahbeeni Zuhair Z Hagos Samya T ST Al-Ahmadi Wijdan W Nadeef Seba S Maddirevula Sateesh S Khabar Khalid S A KSA Putra Alexander A Angelov Angel A Park Changsook C Reyes-Ramos Ana M AM Umer Husen H Ullah Ikram I Driguez Patrick P Fukasawa Yoshinori Y Cheung Ming Sin MS Gallouzi Imed Eddine IE Alkuraya Fowzan S FS
Genome medicine 20231214 1
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Likely causal variants ...[more]