Dataset Information

Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.

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

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Publications

Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.

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]

PMID: 38098057

Similar Datasets

Project description:BackgroundMutations within the genes PRKN and PINK1 are the leading cause of early onset autosomal recessive Parkinson's disease (PD). However, the genetic cause of most early-onset PD (EOPD) cases still remains unresolved. Long-read sequencing has successfully identified many pathogenic structural variants that cause disease, but this technology has not been widely applied to PD. We recently identified the genetic cause of EOPD in a pair of monozygotic twins by uncovering a complex structural variant that spans over 7 Mb, utilizing Oxford Nanopore Technologies (ONT) long-read sequencing. In this study, we aimed to expand on this and assess whether a second variant could be detected with ONT long-read sequencing in other unresolved EOPD cases reported to carry one heterozygous variant in PRKN or PINK1.MethodsONT long-read sequencing was performed on patients with one reported PRKN/PINK1 pathogenic variant. EOPD patients with an age at onset younger than 50 were included in this study. As a positive control, we also included EOPD patients who had already been identified to carry two known PRKN pathogenic variants. Initial genetic testing was performed using either short-read targeted panel sequencing for single nucleotide variants and multiplex ligation-dependent probe amplification (MLPA) for copy number variants.Results48 patients were included in this study (PRKN "one-variant" n = 24, PINK1 "one-variant" n = 12, PRKN "two-variants" n = 12). Using ONT long-read sequencing, we detected a second pathogenic variant in six PRKN "one-variant" patients (26%, 6/23) but none in the PINK1 "one-variant" patients (0%, 0/12). Long-read sequencing identified one case with a complex inversion, two instances of structural variant overlap, and three cases of duplication. In addition, in the positive control PRKN "two-variants" group, we were able to identify both pathogenic variants in PRKN in all the patients (100%, 12/12).ConclusionsThis data highlights that ONT long-read sequencing is a powerful tool to identify a pathogenic structural variant at the PRKN locus that is often missed by conventional methods. Therefore, for cases where conventional methods fail to detect a second variant for EOPD, long-read sequencing should be considered as an alternative and complementary approach.

Dataset Information

Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.

Background

Methods

Results

Conclusions

Publications

Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases.

Similar Datasets

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