%0 Journal Article
%T Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.
%A AlAbdi L
%A Shamseldin HE
%A Khouj E
%A Helaby R
%A Aljamal B
%A Alqahtani M
%A Almulhim A
%A Hamid H
%A Hashem MO
%A Abdulwahab F
%A Abouyousef O
%A Jaafar A
%A Alshidi T
%A Al-Owain M
%A Alhashem A
%A Al Tala S
%A Khan AO
%A Mardawi E
%A Alkuraya H
%A Faqeih E
%A Afqi M
%A Alkhalifi S
%A Rahbeeni Z
%A Hagos ST
%A Al-Ahmadi W
%A Nadeef S
%A Maddirevula S
%A Khabar KSA
%A Putra A
%A Angelov A
%A Park C
%A Reyes-Ramos AM
%A Umer H
%A Ullah I
%A Driguez P
%A Fukasawa Y
%A Cheung MS
%A Gallouzi IE
%A Alkuraya FS
%J Genome Med
%V 15
%N 1
%D 2023 Dec 14
%M 38098057
%F 15.266
%R 10.1186/s13073-023-01270-8
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.