RIPOR2: A new gene of non-syndromic cochleovestibular dysfunction, discrepancy between human pathology and animal models.

Cochleovestibular dysfunctions are rare conditions misrecognized. A homozygous pathogenic variation c.1561C > T (p.Arg521*) in RIPOR2 (RHO family interacting cell polarization regulator 2) has been identified by WES in Tunisian siblings suffering from congenital bilateral profound hearing and vestibular dysfunctions. In contrast to the vestibular areflexia observed in our patients, deaf Ripor2 KO mouse model and our zebrafish model have normal vestibular function.

A 22q13.1 duplication in mosaicism including SOX10.

Waardenburg syndrome (WS) is characterized by the association of sensorineural hearing loss and pigmentation abnormalities. Among the four types, WS Type 2 (WS2) is the only one without a remarkable distinguishing feature. Here, we report a patient initially diagnosed with WS2 who exhibits a 446 kb mosaic duplication in chromosome 22q13.1, encompassing SOX10, and detected using whole genome sequencing in a trio. The patient, a 46,XY boy, presents with profound bilateral sensorineural hearing loss, right heterochromia iridium, left bright blue iris, and skin-depigmented areas in the abdomen and limbs. Vestibular and imaging tests are normal, without inner ear or olfactory bulb malformations. Bilateral cochlear implantation did not prevent language and speech delays. Moderate congenital chronic constipation and neurodevelopmental difficulties were also present. Given the few genes included in this duplicated region (only one OMIM gene with dominant inheritance), this report provides further delineation of the phenotype related to duplications encompassing the entire SOX10 gene.

Genetic Evaluation of Prelingual Hearing Impairment: Recommendations of an European Network for Genetic Hearing Impairment.

The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...].

Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.

Recurrent Benign Paroxysmal Positional Vertigo in DFNB16 Patients with Biallelic STRC Gene Deletions.

OBJECTIVE: Deletions of STRC gene (DFNB16) account for 12% of isolated congenital mild to moderate hearing loss (HL). In mice, the stereocilin protein, encoded by STRC , is present in the vestibular kinocilium embedded in the otoconial membrane of the utricular macula. Despite this, effects on vestibular function have not been widely investigated. The aim of this study was to investigate the prevalence of benign paroxysmal positional vertigo (BPPV) in a cohort of DFNB16 patients. STUDY DESIGN: Observational descriptive epidemiological study. SETTING: Single-center study, in a tertiary referral center. PATIENTS: Older than 5 years, with a genetic diagnosis of HL related to biallelic STRC gene deletions, diagnosed between 2015 and 2021. INTERVENTION: Patients or their parents were interviewed to determine whether they had experienced vertigo or episodes of BPPV. MAIN OUTCOME MEASURE: Criteria were at least five acute episodes of rotatory vertigo, each lasting less than 1 minute, episodes triggered by changes in specific head position, and an absence of neurological symptoms. RESULTS: Sixty-four patients having mild (33%) to moderate (66%) HL were included. Median age was 15 years (range, 6-48 yr). Prevalence of BPPV was 39% (25 of 64). Median age of first onset was 13 years (range, 3-18 yr). CONCLUSIONS: This study showed recurrent BPPV and early age of onset in patients with biallelic STRC gene deletions. BPPV may be associated with the HL phenotype in patients with STRC gene deletions. It is important to inform patients and families of this potential risk such that appropriate management can be proposed.

Congenital posterior cervical spine malformation due to biallelic c.240-4T>G RIPPLY2 variant: A discrete entity.

The clinical and radiological spectrum of spondylocostal dysostosis syndromes encompasses distinctive costo-vertebral anomalies. RIPPLY2 biallelic pathogenic variants were described in two distinct cervical spine malformation syndromes: Klippel-Feil syndrome and posterior cervical spine malformation. RIPPLY2 is involved in the determination of rostro-caudal polarity and somite patterning during development. To date, only four cases have been reported. The current report aims at further delineating the posterior malformation in three new patients. Three patients from two unrelated families underwent clinical and radiological examination through X-ray, 3D computed tomography and brain magnetic resonance imaging. After informed consent was obtained, family-based whole exome sequencing (WES) was performed. Complex vertebral segmentation defects in the cervico-thoracic spine were observed in all patients. WES led to the identification of the homozygous splicing variant c.240-4T>G in all subjects. This variant is predicted to result in aberrant splicing of Exon 4. The current report highlights a subtype of cervical spine malformation with major atlo-axoidal malformation compromising spinal cord integrity. This distinctive mutation-specific pattern of malformation differs from Klippel-Feil syndrome and broadens the current classification, defining a sub-type of RIPPLY2-related skeletal disorder. Of note, the phenotype of one patient overlaps with oculo-auriculo-vertebral spectrum disorder.