Dual Genetic Diagnosis of Prader–Willi Syndrome and TMC1-Related Severe Congenital Hearing Loss: Diagnostic Challenges and Cochlear Implant Outcomes

TL;DR

A child with Prader–Willi syndrome and severe hearing loss was found to have a separate genetic cause, leading to successful cochlear implant outcomes.

Contribution

First molecularly confirmed case of Prader–Willi syndrome co-occurring with TMC1-related hearing loss, highlighting diagnostic and treatment implications.

Findings

Compound heterozygous TMC1 variants were identified as the cause of severe congenital hearing loss in a child with Prader–Willi syndrome.

Cochlear implantation at ages 14 and 20 months led to measurable improvements in hearing and speech development over four years.

The case emphasizes the importance of genomic evaluation to detect blended phenotypes and guide precision care in rare disorders.

Abstract

Background and Clinical Significance: Prader–Willi syndrome (PWS) is an imprinting disorder not typically associated with severe congenital sensorineural hearing loss (SNHL). When profound SNHL is present in an infant with a known syndrome, an independent monogenic etiology should be considered. We report the first molecularly confirmed case of PWS co-occurring with biallelic pathogenic TMC1 variants causing congenital SNHL, outlining diagnostic challenges, cochlear implant (CI) outcomes, and implications for blended phenotypes. Case Presentation: A male infant with PWS due to a paternal 15q11.2–q13 deletion failed newborn hearing screening. Diagnostic auditory brainstem response and auditory steady-state response confirmed bilateral severe-to-profound SNHL. Temporal bone CT/MRI were normal. Comprehensive genetic testing identified compound heterozygous TMC1 variants consistent with autosomal recessive DFNB7/11 hearing loss, plus two variants of uncertain significance in SERPINB6 and EPS8L2. Sequential bilateral cochlear implantation was performed (left ear at 14 months, right at 20 months), followed by auditory–verbal therapy. Over four years, the child showed steady improvements in hearing and early-speech development. Conclusions: Early genomic evaluation is essential when clinical features appear atypical for a known syndrome. Identifying TMC1-related deafness enabled timely cochlear implantation and measurable gains. This case highlights that severe congenital SNHL in a syndromic infant may reflect a distinct monogenic disorder rather than phenotypic expansion of the primary syndrome, emphasizing the importance of recognizing blended phenotypes to guide precision-care strategies in rare disorders.

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