Biallelic mutations in P4HTM cause syndromic obesity

 We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carried pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity, using an in-house computational staged approach. This included analysis of whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistani PROMIS study, and 200K participants of the UK Biobank, to prioritize genes harbouring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding Prolyl 4-Hydroxylase Transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment and/or developmental delay. Three of the five probands died of pneumonia during the ~2 years of the follow up. P4HTM deficiency is a novel form of syndromic obesity affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia inducible factor that is necessary for survival and adaptation under oxygen deprivation but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.