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

Sensorineural hearing loss (SNHL) is one of the most common sensory deficits worldwide, and genetic factors contribute to at least 50-60% of the congenital hearing loss cases. The transmembrane channel-like protein 1 (TMC1) gene has been linked to autosomal recessive (DFNB7/11) and autosomal dominant (DFNA36) non-syndromic hearing loss, and it is a relatively common genetic cause of SNHL. Here, we report eight Finnish families with 11 affected family members with either recessively inherited homozygous or compound heterozygous TMC1 variants associated with congenital moderate-to-profound hearing loss, or a dominantly inherited heterozygous TMC1 variant associated with postlingual progressive hearing loss. We show that the TMC1 c.1534C>T, p.(Arg512*) variant is likely a founder variant that is enriched in the Finnish population. We describe a novel recessive disease-causing TMC1 c.968A>G, p.(Tyr323Cys) variant. We also show that individuals in this cohort who were diagnosed early and received timely hearing rehabilitation with hearing aids and cochlear implants (CI) have reached good speech perception in noise. Comparison of the genetic data with the outcome of CI rehabilitation increases our understanding of the extent to which underlying pathogenic gene variants explain the differences in CI rehabilitation outcomes

Childhood hearing impairment in northern Finland:prevalence, aetiology and additional disabilities

Abstract The purpose of this study was to determine the prevalence and aetiology of childhood hearing impairment (HI) in northern Finland and to evaluate the presence of additional disabilities among hearing impaired children. Such data would be valuable in guiding examinations and rehabilitation. Study I consisted of 214 children with mild to profound HI ascertained prior to age 10 years. They belonged to the birth cohort spanning the years 1993–2002. The clinical data were collected from the patient records of the Oulu University Hospital. In studies II–III, mutations in mitochondrial DNA (mtDNA) and in the WFS1 gene were determined in children with unknown aetiology of HI. Study IV is a prospective follow-up study examining the hearing of children with m.1555A>G mutation in mtDNA. The prevalence of childhood HI was 2.3/1000 live births. Genetic causes were the most common (47%) aetiology of HI, while 16% of cases were acquired and 36% were unknown. Almost 40% of 214 children had one or more additional disabilities that adversely influenced their development or learning. The frequency of additional disabilities was not associated with the severity of HI. Children with acquired HI had additional disabilities more often (66%) than children with genetic or unknown aetiology of HI (44%). Molecular analysis revealed that mutations in mtDNA and WFS1 are rare causes of childhood HI. Three rare variants and the novel p.Gly831Ser variant were found in WFS1. The p.Gly831Ser variant may be a new member to the group of heterozygous WFS1 mutations that lead to HI. One child harboured the pathogenic m.1555A>G mutation in MT-RNR1. In addition, eight rare variants and 13 polymorphisms were found in MT-RNR1 or in MT-RNR2. Evaluation of m.990T>C suggested that this transition is a pathogenic rather than a neutral variant. During a 7.8 year follow up of 19 children with m.1555A>G, HI was ascertained in 10 children (age range, 2.1–13.2 years at the end of the follow-up). Distinct phenotypes of HI were identified. Environmental factors contributing to the phenotype variation were not recognized. Because these children generally pass the newborn hearing screening, it is important to follow over time the hearing of children in families with the m.1555A>G mutation.Tiivistelmä Tämän työn tavoitteena oli tutkia lapsuusiän kuulovikojen esiintyvyyttä ja etiologiaa pohjoissuomalaisilla lapsilla sekä selvittää kuulovikaisilla lapsilla esiintyviä muita oireita. Tieto kuulovian etiologiasta ja mahdollisista muista oireista auttaa tutkimusten ja kuntoutuksen suunnittelussa. Tutkimukseen osallistuvat lapset olivat syntyneet Pohjois-Suomessa vuosina 1993–2002. Osatyössä I kerättiin sairauskertomustiedot niistä lapsista, joiden kuulovika oli todettu ennen kymmenen vuoden ikää. Osatöissä II ja III määritettiin mitokondrion DNA:n ja tuman WFS1-geenin muutoksia lapsilla, joiden kuulovian etiologia oli tuntematon. Osatyössä IV seurattiin lasten kuuloa suvussa, jossa on todettu mitokondrion DNA:n mutaatio m.1555A>G. Lapsuusiän kuulovikojen esiintyvyys oli 2,3 tuhatta vastasyntynyttä kohden. Kuulovian yleisin syy oli perinnöllinen (47 %). Hankinnaisia kuulovikoja oli 16 % ja etiologialtaan tuntemattomia 36 %. Lähes 40 %:lla 214 lapsesta oli kuulovian lisäksi yksi tai useampi muu oire, jonka arvioitiin vaikuttaneen haitallisesti lapsen kehitykseen tai oppimiseen. Muiden oireiden esiintyminen ei riippunut kuulovian vaikeusasteesta. Hankinnaiseksi luokiteltuihin kuulovikoihin liittyi enemmän muita oireita (66 %) kuin niihin kuulovikoihin, joiden syy oli perinnöllinen tai tuntematon (44 %). Pohjoissuomalaisilla lapsilla mitokondrion DNA:n ja WFS1-geenin muutokset olivat harvinaisia kuulovian syitä. WFS1-geenissä todettiin kolme aikaisemmin tunnettua harvinaista ja yksi uusi geenimuutos. Tämän p.Gly831Ser-mutaation arvioitiin olevan heterotsygoottisena kuulovikaa aiheuttava muutos. Yhdellä lapsella todettiin mitokondrion DNA:n patogeeninen mutaatio m.1555A>G. Lisäksi MT-RNR1- ja MT-RNR2-geeneissä todettiin 13 polymorfiaa, jotka kuuluvat normaaliin vaihteluun ja kahdeksan harvinaista muutosta, joista m.990T>C-muutos on todennäköisesti kuulovikaa aiheuttava. Seurantatutkimukseen osallistui 19 lasta, joilla oli m.1555A>G-mutaatio. Seuranta kesti 7,8 vuotta, ja sen aikana ilmaantui kuulovika 10 lapselle, joiden ikä tutkimuksen loppuessa oli 2,1–13,2 vuotta. Todetut kuuloviat olivat keskenään erilaisia. Vaihtelua selittäviä ympäristötekijöitä ei todettu. Lasten kuuloa on tärkeää seurata perheissä, joissa on m.1555A>G-mutaatio, koska lapset yleensä läpäisevät vastasyntyneen kuulonseulontatutkimuksen ja mahdollinen kuulovika kehittyy myöhemmin

A novel frameshift variant in CEP78 associated with nonsyndromic retinitis pigmentosa, and a review of CEP78-related phenotypes

Abstract Background: Pathogenic variants in the CEP78 gene can present as atypical Usher syndrome or as retinitis pigmentosa. Here, we present a review of all reported cases of CEP78 variants in the literature to date and present a novel variant of CEP78, c.1261_1262delinsA, in a consanguineous northern Finnish family with two individuals. Materials and methods: Our patients were first discovered in a registry-based study. Later, they gave their written consent for this study. In order to describe the genotype and phenotype, their historic clinical patient data and genetic data were gathered, and a clinical ophthalmic examination and an audiogram were performed. For this review, a PubMed search using the keyword CEP78 was carried out. The first article on CEP78 was published in the year 2007, and the publications from the years 2007–2021 were included. Results: A large gene panel identified a homozygous CEP78 c.1261_1262delinsA variant in two affected siblings. In addition to the classical signs of retinitis pigmentosa, both siblings had large round atrophic spots in the mid periphery, and hyperautofluorescence of the macula. Patient 1 had age-related hearing impairment; patient 2 had normal hearing. In total, 20 articles have been published about CEP78. Eight of these papers report patient data with the affected individuals typically having retinal dystrophy combined with sensorineural hearing impairment, classified as atypical Usher syndrome. Conclusions: Here, we present a comprehensive review of CEP78 and expand the knowledge of pathogenic CEP78 variants and the phenotypic variety

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

Sensorineural hearing loss (SNHL) is one of the most common sensory deficits worldwide, and genetic factors contribute to at least 50–60% of the congenital hearing loss cases. The transmembrane channel-like protein 1 (TMC1) gene has been linked to autosomal recessive (DFNB7/11) and autosomal dominant (DFNA36) non-syndromic hearing loss, and it is a relatively common genetic cause of SNHL. Here, we report eight Finnish families with 11 affected family members with either recessively inherited homozygous or compound heterozygous TMC1 variants associated with congenital moderate-to-profound hearing loss, or a dominantly inherited heterozygous TMC1 variant associated with postlingual progressive hearing loss. We show that the TMC1 c.1534C>T, p.(Arg512*) variant is likely a founder variant that is enriched in the Finnish population. We describe a novel recessive disease-causing TMC1 c.968A>G, p.(Tyr323Cys) variant. We also show that individuals in this cohort who were diagnosed early and received timely hearing rehabilitation with hearing aids and cochlear implants (CI) have reached good speech perception in noise. Comparison of the genetic data with the outcome of CI rehabilitation increases our understanding of the extent to which underlying pathogenic gene variants explain the differences in CI rehabilitation outcomes

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

Sensorineural hearing loss (SNHL) is one of the most common sensory deficits worldwide, and genetic factors contribute to at least 50&ndash;60% of the congenital hearing loss cases. The transmembrane channel-like protein 1 (TMC1) gene has been linked to autosomal recessive (DFNB7/11) and autosomal dominant (DFNA36) non-syndromic hearing loss, and it is a relatively common genetic cause of SNHL. Here, we report eight Finnish families with 11 affected family members with either recessively inherited homozygous or compound heterozygous TMC1 variants associated with congenital moderate-to-profound hearing loss, or a dominantly inherited heterozygous TMC1 variant associated with postlingual progressive hearing loss. We show that the TMC1 c.1534C&gt;T, p.(Arg512*) variant is likely a founder variant that is enriched in the Finnish population. We describe a novel recessive disease-causing TMC1 c.968A&gt;G, p.(Tyr323Cys) variant. We also show that individuals in this cohort who were diagnosed early and received timely hearing rehabilitation with hearing aids and cochlear implants (CI) have reached good speech perception in noise. Comparison of the genetic data with the outcome of CI rehabilitation increases our understanding of the extent to which underlying pathogenic gene variants explain the differences in CI rehabilitation outcomes

Pathogenic REST variant causing Jones syndrome and a review of the literature

Abstract Jones syndrome is a rare dominantly inherited syndrome characterized by gingival fibromatosis and progressive sensorineural hearing loss becoming symptomatic in the second decade of life. Here, we report a father and his two daughters presenting with a typical Jones syndrome (OMIM %135550) phenotype. Exome sequencing identified a repressor element 1-silencing transcription factor (REST, OMIM *600571) (NM_005612.5) c.2670_2673del p.(Glu891Profs*6) heterozygous variant segregating with Jones syndrome in the family. We review the clinical data from all previously published patients with Jones syndrome and previously published patients with pathogenic REST variants associated with gingival fibromatosis or sensorineural hearing loss. This study suggests that pathogenic REST variants cause Jones syndrome

Clinical and genetic characteristics of Finnish patients with autosomal recessive and dominant non-syndromic hearing loss due to pathogenic TMC1 variants

Abstract Sensorineural hearing loss (SNHL) is one of the most common sensory deficits worldwide, and genetic factors contribute to at least 50–60% of the congenital hearing loss cases. The transmembrane channel-like protein 1 (TMC1) gene has been linked to autosomal recessive (DFNB7/11) and autosomal dominant (DFNA36) non-syndromic hearing loss, and it is a relatively common genetic cause of SNHL. Here, we report eight Finnish families with 11 affected family members with either recessively inherited homozygous or compound heterozygous TMC1 variants associated with congenital moderate-to-profound hearing loss, or a dominantly inherited heterozygous TMC1 variant associated with postlingual progressive hearing loss. We show that the TMC1 c.1534C>T, p.(Arg512*) variant is likely a founder variant that is enriched in the Finnish population. We describe a novel recessive disease-causing TMC1 c.968A>G, p.(Tyr323Cys) variant. We also show that individuals in this cohort who were diagnosed early and received timely hearing rehabilitation with hearing aids and cochlear implants (CI) have reached good speech perception in noise. Comparison of the genetic data with the outcome of CI rehabilitation increases our understanding of the extent to which underlying pathogenic gene variants explain the differences in CI rehabilitation outcomes