Exploring the Missing Heritability in Subjects With Hearing Loss, Enlarged Vestibular Aqueducts, and A Single or No Pathogenic SLC26A4 Variant

Abstract Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype-phenotype correlation, a significant part of SLC26A4 cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, short- and long-read whole genome sequencing and optical genome mapping were performed. We found a previously described EVA-associated haplotype (Caucasian EVA (CEVA)) to be significantly enriched in our M1 patient cohort. The haplotype was also present in two M0 cases. Despite extensive genetic analyses, we were not able to prioritize any of the variants present within the haplotype as the likely pathogenic defect, and therefore additional analyses addressing the defect(s) at the RNA, protein, or epigenetic level are required. Whole genome sequencing also revealed splice-altering SLC26A4 variants in two M1 cases, which are now genetically explained, but no deep-intronic or copy number variants. With these findings, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases.

Download Full-text

Exploring the missing heritability in subjects with hearing loss, enlarged vestibular aqueducts, and a single or no pathogenic SLC26A4 variant

Human Genetics ◽

10.1007/s00439-021-02336-6 ◽

2021 ◽

Author(s):

Jeroen J. Smits ◽

Suzanne E. de Bruijn ◽

Cornelis P. Lanting ◽

Jaap Oostrik ◽

Luke O’Gorman ◽

...

Keyword(s):

Hearing Loss ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genome Mapping ◽

Whole Genome ◽

Missing Heritability ◽

Single Nucleotide Variants ◽

Vestibular Aqueduct ◽

Pathogenic Variants ◽

Long Read

AbstractPathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype–phenotype correlation, a significant part of cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, we first determined the presence of the previously described EVA-associated haplotype (Caucasian EVA (CEVA)), characterized by 12 single nucleotide variants located upstream of SLC26A4. We found this haplotype and a delimited V1-CEVA haplotype to be significantly enriched in our M1 patient cohort (10/16 cases). The CEVA haplotype was also present in two M0 cases (2/12). Short- and long-read whole genome sequencing and optical genome mapping could not prioritize any of the variants present within the CEVA haplotype as the likely pathogenic defect. Short-read whole-genome sequencing of the six M1 cases without this haplotype and the two M0/CEVA cases only revealed previously overlooked or misinterpreted splice-altering SLC26A4 variants in two cases, who are now genetically explained. No deep-intronic or structural variants were identified in any of the M1 subjects. With this study, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases. For pinpointing the pathogenic effect of the CEVA haplotype, additional analyses are required addressing defect(s) at the RNA, protein, or epigenetic level.

Download Full-text

An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs

Human Molecular Genetics ◽

10.1093/hmg/ddaa112 ◽

2020 ◽

Vol 29 (13) ◽

pp. 2250-2260 ◽

Cited By ~ 1

Author(s):

Nicola Bedoni ◽

Mathieu Quinodoz ◽

Michele Pinelli ◽

Gerarda Cappuccio ◽

Annalaura Torella ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Autosomal Recessive Disorder ◽

Severe Form ◽

Chromosome 1 ◽

Whole Genome ◽

Leber Congenital Amaurosis ◽

Pathogenic Variants ◽

Long Read ◽

Biallelic Mutations

Abstract We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients’ fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. Pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic Leber congenital amaurosis (LCA). However, no patient with null biallelic mutations has ever been described, and murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality.

Download Full-text

0306 Exploring the feasibility of using copy number variants as genetic markers through large-scale whole genome sequencing experiments

Journal of Animal Science ◽

10.2527/jam2016-0306 ◽

2016 ◽

Vol 94 (suppl_5) ◽

pp. 146-146

Author(s):

D. M. Bickhart ◽

L. Xu ◽

J. L. Hutchison ◽

J. B. Cole ◽

D. J. Null ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genetic Markers ◽

Genome Sequencing ◽

Copy Number ◽

Large Scale ◽

Copy Number Variants ◽

Whole Genome

Download Full-text

Long-read whole-genome sequencing identified a partial MBD5 deletion in an exome-negative patient with neurodevelopmental disorder

Journal of Human Genetics ◽

10.1038/s10038-020-00893-8 ◽

2021 ◽

Author(s):

Sachiko Ohori ◽

Rie S. Tsuburaya ◽

Masako Kinoshita ◽

Etsuko Miyagi ◽

Takeshi Mizuguchi ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Neurodevelopmental Disorder ◽

Whole Genome ◽

Negative Patient ◽

Long Read

Download Full-text

Abstract 343: Bayesian Selection of Modifier Genes in Hypertrophic Cardiomyopathy Through Whole Genome Sequencing

Circulation Research ◽

10.1161/res.117.suppl_1.343 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Matthew Wheeler ◽

Daryl Waggott ◽

Megan Grove ◽

Frederick Dewey ◽

Cuiping Pan ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

A Priori ◽

Copy Number Variants ◽

Whole Genome Sequence ◽

Monogenic Disease ◽

Whole Genome ◽

Genetic Modifiers ◽

Structural Variants

Background: Technological advances have greatly reduced the cost of whole genome sequencing. For single individuals clinical application is apparent, while exome sequencing in tens of thousands of people has allowed a more global view of genetic variation that can inform interpretation of specific variants in individuals. We hypothesized that genome sequencing of patients with monogenic cardiomyopathy would facilitate discovery of genetic modifiers of phenotype. Methods and Results: We identified 48 individuals diagnosed with cardiomyopathy and with putative mutations in MYH7, the gene encoding beta myosin heavy chain. We carried out whole genome sequencing and applied a newly developed analytical pipeline optimized for discovery of genes modifying severity of clinical presentation and outcomes. Using a combination of external priors and rare variant burden tests we scored genes as potential modifiers. There were 96 genes that reached a modifier score of 6 out of 12 or better (9=2, 8=8, 7=17, 6=69). We identified NCKAP1, a gene that regulates actin filament dynamics, and CAMSAP1, a calmodulin regulate gene that regulates microtubule dynamics, as top scoring modifiers of hypertrophic cardiomyopathy phenotypes (score=9) while LDB2, RYR2, FBN1 and ATP1A2 had modifier scores of 8. Of the top scoring genes, 21 out of 96 were identified as candidates a priori. Our candidate prioritization scheme identified the previously described modifiers of cardiomyopathy phenotype, FHOD3 and MYBPC3, as top scoring genes. We identified structural variants in 21 clinically sequenced cardiomyopathy associated genes, 13 of which were at less than 10% frequency. Copy number variants in ILK and CSRP3 were nominally associated with ejection fraction (p=0.03), while 8 genes showed copy gains (GLA, FKTN, SGCD, TTN, SOS1, ANKRD1, VCL and NEBL). Structural variants were found in CSRP3, MYL3 and TNNC1, all of which have been implicated as causative for HCM. Conclusion: Evaluation of the whole genome sequence, even in the case of putatively monogenic disease, leads to important diagnostic and scientific insights not revealed by panel-based sequencing.

Download Full-text

Detecting a long insertion variant in SAMD12 by SMRT sequencing: implications of long-read whole-genome sequencing for repeat expansion diseases

Journal of Human Genetics ◽

10.1038/s10038-018-0551-7 ◽

2018 ◽

Vol 64 (3) ◽

pp. 191-197 ◽

Cited By ~ 12

Author(s):

Takeshi Mizuguchi ◽

Tomoko Toyota ◽

Hiroaki Adachi ◽

Noriko Miyake ◽

Naomichi Matsumoto ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Repeat Expansion ◽

Whole Genome ◽

Smrt Sequencing ◽

Long Read

Download Full-text

Detection and characterization of copy number variants based on whole-genome sequencing by DNBSEQ platforms

10.1101/786962 ◽

2019 ◽

Author(s):

Junhua Rao ◽

Lihua Peng ◽

Fang Chen ◽

Hui Jiang ◽

Chunyu Geng ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Copy Number ◽

Copy Number Variants ◽

Copy Number Variant ◽

Whole Genome ◽

Genome Wide ◽

Wide Range ◽

Distribution Sensitivity ◽

Cnv Detection

AbstractBackgroundNext-generation sequence (NGS) has rapidly developed in past years which makes whole-genome sequencing (WGS) becoming a more cost- and time-efficient choice in wide range of biological researches. We usually focus on some variant detection via WGS data, such as detection of single nucleotide polymorphism (SNP), insertion and deletion (Indel) and copy number variant (CNV), which playing an important role in many human diseases. However, the feasibility of CNV detection based on WGS by DNBSEQ™ platforms was unclear. We systematically analysed the genome-wide CNV detection power of DNBSEQ™ platforms and Illumina platforms on NA12878 with five commonly used tools, respectively.ResultsDNBSEQ™ platforms showed stable ability to detect slighter more CNVs on genome-wide (average 1.24-fold than Illumina platforms). Then, CNVs based on DNBSEQ™ platforms and Illumina platforms were evaluated with two public benchmarks of NA12878, respectively. DNBSEQ™ and Illumina platforms showed similar sensitivities and precisions on both two benchmarks. Further, the difference between tools for CNV detection was analyzed, and indicated the selection of tool for CNV detection could affected the CNV performance, such as count, distribution, sensitivity and precision.ConclusionThe major contribution of this paper is providing a comprehensive guide for CNV detection based on WGS by DNBSEQ™ platforms for the first time.

Download Full-text

Whole-Genome Sequencing Improves the Diagnosis of DFNB1 Monoallelic Patients

Genes ◽

10.3390/genes12081267 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1267

Author(s):

Anaïs Le Nabec ◽

Mégane Collobert ◽

Cédric Le Maréchal ◽

Rémi Marianowski ◽

Claude Férec ◽

...

Keyword(s):

Hearing Loss ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Gjb2 Gene ◽

Whole Genome ◽

Genetic Origin ◽

Functional Assays ◽

Syndromic Hearing Loss ◽

Sensory Defect

Hearing loss is the most common sensory defect, due in most cases to a genetic origin. Variants in the GJB2 gene are responsible for up to 30% of non-syndromic hearing loss. Today, several deafness genotypes remain incomplete, confronting us with a diagnostic deadlock. In this study, whole-genome sequencing (WGS) was performed on 10 DFNB1 patients with incomplete genotypes. New variations on GJB2 were identified for four patients. Functional assays were realized to explore the function of one of them in the GJB2 promoter and confirm its impact on GJB2 expression. Thus, in this study WGS resolved patient genotypes, thus unlocking diagnosis. WGS afforded progress and bridged some gaps in our research.

Download Full-text