Article
Author: Hakami, Wejdan S. ; Shabbir, Muhammad I ; Zaki, Maha S ; Zifarelli, Giovanni ; Alhashem, Abdullah M. ; Karimiani, Ehsan G. ; McGavin, Lucy ; Ghani, Shamsul ; Leslie, Joseph S ; Zaki, Maha S. ; Owrang, Daniel ; Ebner, Michael ; Karimiani, Ehsan G ; Alavi, Shahryar ; Gleeson, Joseph G. ; Alhashem, Abdullah M ; Ahmad, Faraz ; Crosby, Andrew H. ; Rodriguez Cruz, Pedro M ; Vona, Barbara ; Baple, Emma L. ; Gleeson, Joseph G ; Wright, Caroline F ; Al-Futaisi, Amna ; Diop, Amadou G ; Saberi, Alihossein ; Tajsharghi, Homa ; Crosby, Andrew H ; Salazar-Villacorta, Ainara ; Burglen, Lydie ; Gunning, Adam C. ; Shabbir, Muhammad I. ; Haucke, Volker ; Houlden, Henry ; Maroofian, Reza ; Elpeleg, Orly ; Diop, Amadou G. ; Najjar, Marwan ; Khan, Nasar ; Khan, Hamid ; Cannon, Stuart J ; Cannon, Stuart J. ; Scardamaglia, Annarita ; Zamani, Mina ; Rawlins, Lettie E ; Boustany, Rose-Mary N. ; Khan, Amjad ; Hashem, Amal M Al ; Al-Kindi, Adila ; Hamid, Mohammad ; Daana, Muhannad ; Obeid, Makram ; Baple, Emma L ; Cloarec, Robin ; Owens, Martina ; Rawlins, Lettie E. ; Leslie, Joseph S. ; Beydoun, Ahmad ; Shariati, Gholamreza ; Bauer, Peter ; Salah, Somaya ; Ndiaye, Moustapha ; Khan, Shujaat Ali ; Al Hashem, Amal M ; Hakami, Wejdan S ; Galehdari, Hamid ; Gunning, Adam C ; Rodriguez Cruz, Pedro M. ; Sadeghian, Saeid ; Umair, Muhammad ; Boustany, Rose-Mary N ; Wright, Caroline F. ; Al-Maawali, Almundher ; Milh, Mathieu ; Sedaghat, Alireza ; Azizimalamiri, Reza ; Khan, Jahangir ; Ubeyratna, Nishanka
PURPOSEBiallelic 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.METHODSClinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.RESULTSWe 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.CONCLUSIONOur studies comprehensively characterize INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.