Submission Details

The FITM2 gene is located on chromosome 20 at 20q13.12. It encodes for the fat storage-inducing transmembrane protein 2, embedded in the wall of the endoplasmic reticulum where they regulate lipid droplet formation in the cytosol. *FITM2 *was first reported in relation to autosomal recessive Siddiqi syndrome (SIDDIS) in 2017 (Zazo Seco et al., PMID: 28067622). This disease is caused by homozygous or compound heterozygous mutation in the FITM2 gene. The associated phenotypes involve the nervous system and musculature including hypotonia, global developmental delay, poor fine motor skills, impaired intellectual development, and sensorineural hearing impairment. More variable features may include ichthyosis-like skin abnormalities or sensory neuropathy. Around 5 unique variants (e.g., nonsense, frameshift, and missense) have been reported in at least 4 probands in various publications (PMID: 28067622, 30214770, 30288795, 35754111). A LOF nonsense variant was also found to segregate with the disorder in additional family members with a LOD score of 4.00 (PMID: 28067622). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by experimental evidence in Drosophila (animal model) where RNAi-induced gene downregulation of Fitm gene resulted in severely impaired and uncoordinated locomotion along with sensory neuropathy, thus recapitulating the phenotypic features of Siddiqi syndrome (PMID: 28067622). Symptomatic evidence for dyskinetic cerebral palsy has also been reported in one of the probands (PMID: 30214770).

In summary, there is definitive evidence to support the relationship of the FITM2 gene with Siddiqi syndrome. This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 17/10/2022 (SOP Version 9).