<i>PDZD7</i> and hearing loss: More than just a modifier

Booth, Kevin T.; Azaiez, Héla; Kahrizi, Kimia; Simpson, Allen C.; Tollefson, William T.A.; Sloan, Christina M.; Meyer, Nicole C.; Babanejad, Mojgan; Ardalani, Fariba; Arzhangi, Sanaz; Schnieders, Michael J.; Najmabadi, Hossein; Smith, Richard J.H.

doi:10.1002/ajmg.a.37274

Cited by 56 publications

(70 citation statements)

References 36 publications

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“…31) and PDZD7 32. The most comprehensive previous study was completed on 144 GJB2 -negative subjects using linkage analysis and Sanger sequencing, which identified variants in 10 different genes ( MYO15A , SLC26A4 , ILDR1 , TECTA , TMC1 , DFNB59 , LRTOMT , OTOF , MARVELD2 and MYO7A ) with a diagnosis rate of 22.9% 33.…”

Section: Discussionmentioning

confidence: 99%

Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran

et al. 2015

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Background Countries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes. Design Using a custom targeted genomic enrichment (TGE) panel we simultaneously interrogating all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families. Results We established a genetic diagnosis for 67% of probands and their families, with over half of all diagnoses attributable to variants in five genes: SLC26A4, MYO15A, MYO7A, CDH23, and PCDH15. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and 3 novel copy number variations. Several variants represent founder mutations. Conclusion This study attests to the power of TGE and massively parallel sequencing (TGE+MPS) as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery.

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Section: Discussionmentioning

confidence: 99%

Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran

et al. 2015

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“…In this study, we did not find other functional candidate gene variants of classical Usher syndrome genes by targeted region capture and high throughput sequencing. At present, the oldest patient reported with ARNSHL‐associated PDZD7 biallelic mutations is 38 years old (Table 2), and this patient showed no abnormalities in funduscopy (Booth et al, 2015). In our study, the age of the ARNSHL affected individuals was younger than 11 years of age during examinations.…”

Section: Discussionmentioning

confidence: 99%

“…PDZD7 encodes a PDZ domain‐containing scaffold protein; the largest transcript (NM_001195263.1) of PDZD7 encodes 17 exons, and it has been implicated as an ARNSHL‐associated gene (Booth et al, 2015; Le Quesne Stabej et al, 2017; Schneider et al, 2009; Vona et al, 2016) and a modifier and candidate gene for human USH2 (Ebermann et al, 2010). In this study, next generation sequencing (NGS) was used to find the disease‐causing gene of two Chinese families with ARNSHL (Figure 1a and 1b), and we identified two biallelic mutations in the PDZD7 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Variations in many genes can cause either non‐syndromic hearing loss or syndromic hearing loss. PDZD7 encodes a PDZ domain‐containing scaffold protein, that was recently implicated as a modifier and candidate gene in human USH2 (Ebermann et al, 2010), and it is an autosomal recessive genetic hearing loss (ARNSHL)‐associated gene (Booth et al, 2015; Le Quesne Stabej et al, 2017; Schneider et al, 2009; Vona et al, 2016). The PDZD7 gene was first identified as being responsible for ARNSHL in a consanguineous German family in 2009.…”

Section: Introductionmentioning

confidence: 99%

“…Clinical tracking of this patient over 6 years showed that the proband demonstrated stable sensorineural hearing loss and healthy retinas at the age of 15.5 years (Vona et al, 2016). To date, only seven biallelic mutations of the monogenic PDZD7 have been validated—in two German families, four Iranian families, and a Pakistani family with ARNSHL (Booth et al, 2015; Le Quesne Stabej et al, 2017; Vona et al, 2016). Outside of the Iranian, German and Pakistani populations, little is known about the effect of PDZD7 on ARNSHL.…”

Section: Introductionmentioning

confidence: 99%

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Novel recessive PDZD7 biallelic mutations in two Chinese families with non‐syndromic hearing loss

Guan

Wang

Lan

et al. 2017

American J of Med Genetics Pt A

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Autosomal recessive non‐syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic condition. PDZD7 has emerged as a new genetic etiology of ARNSHL. Biallelic mutations in the PDZD7 gene have been reported in two German families, four Iranian families, and a Pakistani family with ARNSHL. The effect of PDZD7 on ARNSHL in other population has yet to be elucidated. Two Chinese ARNSHL families, each of which had two affected siblings, were included in this study. The families underwent target region capture and high‐throughput sequencing to analyze the exonic, splice‐site, and intronic sequences of 128 genes. Furthermore, 1751 normal Chinese individuals served as controls, and 122 Chinese families segregating with apparent ARNSHL, who had been previously excluded for variants in the common deafness genes GJB2 and SLC26A4, were subjected to screening for candidate mutations. We identified a novel homozygous missense mutation (p.Arg66Leu) and novel compound heterozygous frameshift mutations (p.Arg56fsTer24 and p.His403fsTer36) in Chinese families with ARNSHL. This is the first report to identify PDZD7 as an ARNSHL‐associated gene in the Chinese population. Our finding could expand the pathogenic spectrum and strengthens the clinical diagnostic role of the PDZD7 gene in ARNSHL patients.

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Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy

Walsh

Bell

Chong

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo explore the diagnostic utility and cost effectiveness of whole exome sequencing (WES) in a cohort of individuals with peripheral neuropathy.MethodsSingleton WES was performed in individuals recruited though one pediatric and one adult tertiary center between February 2014 and December 2015. Initial analysis was restricted to a virtual panel of 55 genes associated with peripheral neuropathies. Patients with uninformative results underwent expanded analysis of the WES data. Data on the cost of prior investigations and assessments performed for diagnostic purposes in each patient was collected.ResultsFifty patients with a peripheral neuropathy were recruited (median age 18 years; range 2–68 years). The median time from initial presentation to study enrollment was 6 years 9 months (range 2 months–62 years), and the average cost of prior investigations and assessments for diagnostic purposes AU$4013 per patient. Eleven individuals received a diagnosis from the virtual panel. Eight individuals received a diagnosis following expanded analysis of the WES data, increasing the overall diagnostic yield to 38%. Two additional individuals were diagnosed with pathogenic copy number variants through SNP microarray.ConclusionsThis study provides evidence that WES has a high diagnostic utility and is cost effective in patients with a peripheral neuropathy. Expanded analysis of WES data significantly improves the diagnostic yield in patients in whom a diagnosis is not found on the initial targeted analysis. This is primarily due to diagnosis of conditions caused by newly discovered genes and the resolution of complex and atypical phenotypes.

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PDZD7 and hearing loss: More than just a modifier

Cited by 56 publications

References 36 publications

Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran

Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran

Novel recessive PDZD7 biallelic mutations in two Chinese families with non‐syndromic hearing loss

Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy

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