Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.
Rawlins LE., Maroofian R., Cannon SJ., Daana M., Zamani M., Ghani S., Leslie JS., Ubeyratna N., Khan N., Khan H., Scardamaglia A., Cloarec R., Khan SA., Umair M., Sadeghian S., Galehdari H., Al-Maawali A., Al-Kindi A., Azizimalamiri R., Shariati G., Ahmad F., Al-Futaisi A., Rodriguez Cruz PM., Salazar-Villacorta A., Ndiaye M., Diop AG., Sedaghat A., Saberi A., Hamid M., Zaki MS., Vona B., Owrang D., Alhashem AM., Obeid M., Khan A., Beydoun A., Najjar M., Tajsharghi H., Zifarelli G., Bauer P., Hakami WS., Hashem AMA., Boustany R-MN., Burglen L., Alavi S., Gunning AC., Owens M., Karimiani EG., Gleeson JG., Milh M., Salah S., Khan J., Haucke V., Wright CF., McGavin L., Elpeleg O., Shabbir MI., Houlden H., Ebner M., Baple EL., Crosby AH.
PURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations. METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies. RESULTS: We characterize a clinically variable disorder with cardinal features including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition. CONCLUSION: Our studies comprehensively characterise INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.