FRMPD4, a causal gene for intellectual disability and epilepsy, is associated with X-linked non-syndromic hearing loss.

Authors

Daniel Liedtke, Kristen Rak, Katrina M Schrode, Philip Hehlert, Niloofar Chamanrou, Daniel Bengl, Radoslaw Katana, Soganad Heydaran, Julia Doll, Mei Han, Indrajit Nanda, Pingkalai R Senthilan, Lukas Jürgens, Linda Bieniussa, Johannes Voelker, Cordula Neuner, Michaela Ah Hofrichter, Jörg Schröder, Renske T W Schellens, Erik de Vrieze, Erwin van Wijk, Ulrich Zechner, Stefan Herms, Per Hoffmann, Tobias Müller, Marcus Dittrich, Oliver Bartsch, Peter M Krawitz, Eva Klopocki, Wafaa Shehata-Dieler, Reza Maroofian, Tao Wang, Paul F Worley, Martin C Göpfert, Hamid Galehdari, Amanda M Lauer, Thomas Haaf, Barbara Vona

Published in

medRxiv : the preprint server for health sciences. Mar 30, 2026. Epub Mar 30, 2026.

Abstract

Understanding the phenotypic spectrum of disease-associated genes is essential for accurate diagnosis and targeted therapy. FRMPD4 (FERM and PDZ Domain Containing 4) has previously been associated with intellectual disability and epilepsy. However, its potential role in non-syndromic hearing loss has not been explored.
We performed genetic analysis in two unrelated families presenting with non-syndromic sensorineural hearing loss, identifying maternally inherited missense variants in FRMPD4. Clinical phenotyping included audiological assessment and evaluation for neurodevelopmental involvement. Cross-species expression analyses were conducted in Drosophila, zebrafish, and mouse. Functional characterization included quantitative evaluation of sound-evoked responses in Drosophila nicht gut hörend (ngh) mutants, assessment of neuronal development and acoustic startle responses in zebrafish loss of function models, and morphological cochlear analyses with auditory brainstem response measurements in knockout mice.
Three affected males from two unrelated families presented with prelingual, bilaterally symmetrical sensorineural hearing loss, with confirmed congenital onset in one individual and no evidence of neurodevelopmental abnormalities. Cross-species analyses demonstrated evolutionarily conserved expression of FRMPD4 in auditory structures. In Drosophila, quantitative analysis of sound-evoked responses in ngh mutants revealed impaired auditory function. Zebrafish loss of function models exhibited reduced neuronal populations in the otic vesicle and posterior lateral line, abnormal neuromast development, and diminished acoustic startle responses. In mice, Frmpd4 knockout resulted in high-frequency hearing loss and cochlear abnormalities consistent with the human phenotype.
Our findings expand the phenotypic spectrum of FRMPD4 to include non-syndromic sensorineural hearing loss and establish its evolutionarily conserved role in auditory function. These results have direct implications for genetic diagnosis and variant interpretation in patients with hearing loss.

PMID:
41959831
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.