A homozygous AP3D1 missense variant in patients with sensorineural hearing loss as the leading manifestation

Alexandra Frohne, Martin Koenighofer, Hakan Cetin, Michael Nieratschker, David T. Liu, Franco Laccone, Juergen Neesen, Stefan F. Nemec, Ursula Schwarz-Nemec, Christian Schoefer, Karen B. Avraham, Klemens Frei, Katharina Grabmeier-Pfistershammer, Bernhard Kratzer, Klaus Schmetterer, Winfried F. Pickl, Thomas Parzefall*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Loss-of-function variants in AP3D1 have been linked to Hermansky–Pudlak syndrome (HPS) 10, a severe multisystem disorder characterized by oculocutaneous albinism, immunodeficiency, neurodevelopmental delay, hearing loss (HL), and neurological abnormalities, fatal in early childhood. Here, we report a consanguineous family who presented with presumably isolated autosomal recessive (AR) HL. Whole-exome sequencing was performed on all core family members, and selected patients were screened using array-based copy-number analysis and karyotyping. Candidate variants were validated by Sanger sequencing and assessed in silico. A homozygous, likely pathogenic p.V711I missense variant in AP3D1 segregated with the HL. The family was characterized by thorough medical and laboratory examination. The HL was consistent across patients and accompanied by neurological manifestations in two brothers. The sole female patient was diagnosed with premature ovarian failure. Further findings, including mild neutropenia and reduced NK-cell cytotoxicity in some as well as brain alterations in all homozygous patients, were reminiscent of HPS10, though milder and lacking the characteristic albinism. Previously unrecognized, milder, isolated HL was identified in all heterozygous carriers. A protein model indicates that the variant interferes with protein–protein interactions. These results suggest that a missense variant alters inner-ear-specific functions leading to HL with mild HPS10-like symptoms of variable penetrance. Milder HL in heterozygous carriers may point towards semi-dominant inheritance of this trait. Since all previously reported HPS10 cases were pediatric, it is unknown whether the observed primary ovarian insufficiency recapitulates the subfertility in Ap3d1-deficient mice.

Original languageEnglish
JournalHuman Genetics
StateAccepted/In press - 2022


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