Clinical and Genetic Characteristics of Finnish Patients with Autosomal Recessive and Dominant Non-Syndromic Hearing Loss Due to Pathogenic TMC1 Variants

Kraatari, Minna; Haanpää, Maria K.; Willberg, Tytti; Pohjola, Pia; Keski‐Filppula, Riikka; Kuismin, Outi; Moilanen, Jukka S.; Häkli, Sanna; Rahikkala, Elisa

doi:10.3390/jcm11071837

Cited by 2 publications

(1 citation statement)

References 31 publications

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“…TMC1 gene mutations causing human deafness are divided into two categories: those referred to as DFNA36 (OMIM # 606705), which are autosomal dominant, and those termed DFNB7 (OMIM # 600974), which are autosomal recessive. Nonsense and frameshift mutations of TMC1 predicted to cause a loss of normal protein function through protein truncation are often detected in DFNB7/11 patients (Kraatari‐Tiri et al, 2022 ; Nishio & Usami, 2022 ). Our patient carried a break point in intron 8 of TMC1 , which interrupted the open reading frame.…”

Section: Discussionmentioning

confidence: 99%

11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation

Zhang

Wang

Zhou

et al. 2023

Molec Gen & Gen Med

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BackgroundWe describe a 13‐year‐old girl with a 11q13.3q13.4 deletion encompassing the SHANK2 gene and a 9q21.13q21.33 duplication. She presented with pre‐ and postnatal growth retardation, global developmental delay, severe language delay, cardiac abnormalities, and dysmorphisms. Her maternal family members all had histories of reproductive problems.MethodsMaternal family members with histories of reproductive problems were studied using G‐banded karyotyping and optical genome mapping (OGM). Long‐range PCR (LR‐PCR) and Sanger sequencing were used to confirm the precise break point sequences obtained by OGM.ResultsG‐banded karyotyping characterized the cytogenetic results as 46,XX,der(9)?del(9)(q21q22)t(9;14)(q22;q24),der(11)ins(11;?9)(q13;?q21q22),der(14)t(9;14). Using OGM, we determined that asymptomatic female family members with reproductive problems were carriers of a four‐way balanced chromosome translocation. Their karyotype results were further refined as 46,XX,der(9)del(9)(q21.13q21.33)t(9;14)(q21.33;q22.31),der(11)del(11)(q13.3q13.4)ins(11;9)(q13.3;q21.33q21.13),der(14)t(9:14)ins(14;11)(q23.1;q13.4q13.3). Thus, we confirmed that the affected girl inherited the maternally derived chromosome 11. Furthermore, using LR‐PCR, we showed that three disease‐related genes (TMC1, NTRK2, and KIAA0586) were disrupted by the breakpoints.ConclusionsOur case highlights the importance of timely parental origin testing for patients with rare copy number variations, as well as the accurate characterization of balanced chromosomal rearrangements in families with reproductive problems. In addition, our case demonstrates that OGM is a useful clinical application for analyzing complex structural variations within the human genome.

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Section: Discussionmentioning

confidence: 99%

11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation

Zhang

Wang

Zhou

et al. 2023

Molec Gen & Gen Med

View full text Add to dashboard Cite

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Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment

Aboagye

Adadey

Wonkam‐Tingang

et al. 2023

Genes

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The genetic etiology of non-syndromic hearing impairment (NSHI) is highly heterogeneous with over 124 distinct genes identified. The wide spectrum of implicated genes has challenged the implementation of molecular diagnosis with equal clinical validity in all settings. Differential frequencies of allelic variants in the most common NSHI causal gene, gap junction beta 2 (GJB2), has been described as stemming from the segregation of a founder variant and/or spontaneous germline variant hot spots. We aimed to systematically review the global distribution and provenance of founder variants associated with NSHI. The study protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews, with the registration number “CRD42020198573”. Data from 52 reports, involving 27,959 study participants from 24 countries, reporting 56 founder pathogenic or likely pathogenic (P/LP) variants in 14 genes (GJB2, GJB6, GSDME, TMC1, TMIE, TMPRSS3, KCNQ4, PJVK, OTOF, EYA4, MYO15A, PDZD7, CLDN14, and CDH23), were reviewed. Varied number short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) were used for haplotype analysis to identify the shared ancestral informative markers in a linkage disequilibrium and variants’ origins, age estimates, and common ancestry computations in the reviewed reports. Asia recorded the highest number of NSHI founder variants (85.7%; 48/56), with variants in all 14 genes, followed by Europe (16.1%; 9/56). GJB2 had the highest number of ethnic-specific P/LP founder variants. This review reports on the global distribution of NSHI founder variants and relates their evolution to population migration history, bottleneck events, and demographic changes in populations linked with the early evolution of deleterious founder alleles. International migration and regional and cultural intermarriage, coupled to rapid population growth, may have contributed to re-shaping the genetic architecture and structural dynamics of populations segregating these pathogenic founder variants. We have highlighted and showed the paucity of data on hearing impairment (HI) variants in Africa, establishing unexplored opportunities in genetic traits.

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Clinical and Genetic Characteristics of Finnish Patients with Autosomal Recessive and Dominant Non-Syndromic Hearing Loss Due to Pathogenic TMC1 Variants

Cited by 2 publications

References 31 publications

11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation

11q13.3q13.4 deletion plus 9q21.13q21.33 duplication in an affected girl arising from a familial four‐way balanced chromosomal translocation

Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment

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