{Reference Type}: Journal Article
{Title}: Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.
{Author}: AlAbdi L;Shamseldin HE;Khouj E;Helaby R;Aljamal B;Alqahtani M;Almulhim A;Hamid H;Hashem MO;Abdulwahab F;Abouyousef O;Jaafar A;Alshidi T;Al-Owain M;Alhashem A;Al Tala S;Khan AO;Mardawi E;Alkuraya H;Faqeih E;Afqi M;Alkhalifi S;Rahbeeni Z;Hagos ST;Al-Ahmadi W;Nadeef S;Maddirevula S;Khabar KSA;Putra A;Angelov A;Park C;Reyes-Ramos AM;Umer H;Ullah I;Driguez P;Fukasawa Y;Cheung MS;Gallouzi IE;Alkuraya FS;
{Journal}: Genome Med
{Volume}: 15
{Issue}: 1
{Year}: 2023 Dec 14
{Factor}: 15.266
{DOI}: 10.1186/s13073-023-01270-8
{Abstract}: <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.