FITM2 – Deafness Dystonia Syndrome

This association is supported by evidence from multiple independent families in which loss‑of‑function variants in FITM2 segregate with a characteristic syndrome defined by hearing impairment, dystonia, motor regression, ichthyosis‑like skin changes, and sensory neuropathy (PMID:28067622, PMID:30214770). In the initial report, a consanguineous Pakistani family harbored a homozygous nonsense mutation, c.4G>T (p.Glu2Ter), which was shown to co‐segregate with the disease, thereby establishing a direct link between FITM2 dysfunction and the observed clinical phenotype (PMID:28067622).

The clinical features, including profound hearing impairment (HP:0000365) and sensory neuropathy (HP:0000763), highlight the neurosensory component of the disorder. In addition to the homozygous variant, a subsequent study identified compound heterozygous FITM2 variants, with one allele carrying a similar predicted loss‑of‑function change (c.21C>A (p.Cys7Ter)) along with another variant (c.652C>T (p.Gln218Ter) or c.39dup (p.Thr14fs)), reinforcing the autosomal recessive inheritance pattern (PMID:30214770).

Segregation analysis from these independent families revealed that the affected individuals in each kindred consistently carried biallelic deleterious variants, with additional affected relatives corroborating the inheritance model (PMID:28067622, PMID:30214770). This robust co‐segregation strengthens the genetic evidence linking FITM2 to deafness‑dystonia syndrome.

Genetic evidence is bolstered by the identification of well‐characterized loss‑of‑function alleles, such as c.4G>T (p.Glu2Ter), in affected probands. At least three probands from two independent studies have been documented with FITM2 variants, and the severity of the clinical phenotype corresponds with the predicted impact on protein function, satisfying key ClinGen criteria for a strong genetic association (PMID:28067622, PMID:30214770).

Functional studies further support the role of FITM2 in disease pathogenesis. Downregulation of the FITM2 ortholog in Drosophila using RNA interference recapitulated key aspects of the human phenotype, including progressive locomotor impairment and sensory deficits, thereby providing experimental validation of the genetic findings (PMID:28067622).

In summary, the integration of consistent genetic findings from independent families with supportive functional data confirms a strong association between FITM2 and deafness‑dystonia syndrome. This evidence not only informs diagnostic decision‑making and genetic counseling but also underscores the clinical utility of molecular testing for FITM2 variants in affected individuals.

References

• Disease models & mechanisms • 2017 • A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy PMID:28067622
• Clinical case reports • 2018 • The first case of deafness-dystonia syndrome due to compound heterozygous variants in FITM2 PMID:30214770

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