A homozygousFITM2mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy

Abstract

A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous nonsense mutation, c.4G>T (p.Glu2*), in FITM2 was identified. FITM2 and its paralog FITM1 constitute an evolutionary conserved protein family involved in partitioning of triglycerides into cellular lipid droplets. Despite the role of FITM2 in neutral lipid storage and metabolism, no indications for lipodystrophy were observed in the affected individuals. In order to obtain independent evidence for the involvement of FITM2 in the human pathology, downregulation of the single Fitm ortholog, CG10671, in Drosophila melanogaster was pursued using RNA interference. Characteristics of the syndrome, including progressive locomotor impairment, hearing loss and disturbed sensory functions, were recapitulated in Drosophila, which supports the causative nature of the FITM2 mutation. Mutation-based genetic counseling can now be provided to the family and insight is obtained into the potential impact of genetic variation in FITM2.

First replication that biallelic variants in FITM2 cause a complex deafness‐dystonia syndrome

“…To our knowledge, this is only the second family with a (presumably) pathogenic variant in FITM2 published so far. As, first, the phenotype of our patient is strikingly similar to the case described in the literature, second, the variant segregates with the disease in the family, and third, no other pathogenic variant could be found in the exome‐wide analysis, we have strong reason to believe that we report the first disease‐causing missense variant in FITM2 . Hence, we are adding to the genotypic spectrum and replicated that biallelic variants in FITM2 are responsible for a complex deafness‐dystonia syndrome.…”

“…Recently, the case of a consanguineous family from Pakistan was published, in which 5 of 8 children had limb dystonia, sensorineural hearing impairment, global developmental delay, ichthyosis‐like hyperkeratoses (mainly at the shins), low body mass index, short stature, and signs of sensory polyneuropathy. Whole‐exome sequencing (WES) identified a homozygous nonsense variant in FITM2 , which segregated with the disease in the family …”

FIT2 is a lipid phosphate phosphatase crucial for endoplasmic reticulum homeostasis

“…The selective knockout of murine FIT2 in adipose tissue leads to a progressive lipodystrophy (Miranda et al, 2014). Homozygous FIT2 deficiency in humans was recently reported to cause deafness-dystonia (Zazo Seco et al, 2017). These results indicate that FIT2 has a crucial role in cellular lipid metabolism.…”

“…lethality in model organism knockouts(Choudhary et al, 2015;Goh et al, 2015) and syndromes of deafness and myotonia in humans(Seco et al, 2016).…”

The first case of deafness‐dystonia syndrome due to compound heterozygous variants in FITM2

“…“Siddiqi syndrome” is a proposed deafness‐dystonia syndrome with presumed autosomal recessive inheritance first described by Zazo Seco et al in five of eight Pakistani siblings with consanguineous parents. The affected siblings presented with progressive hearing loss, dystonic limb movements leading to immobility and contractures, failure to thrive, neuropathic pain, and ichthyosis‐like skin findings with scarring alopecia.…”