European Journal of Medical Genetics 65 (2022) 104540 Available online 21 June 2022 1769-7212/© 2022 Elsevier Masson SAS. All rights reserved. Genetic and clinical profle of patients with hypophosphatemic rickets Binata Marik a , Arvind Bagga b , Aditi Sinha b , Priyanka Khandelwal b , Pankaj Hari b , Arundhati Sharma a, * a Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, India b Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India A R T I C L E INFO Keywords: Fibroblast growth factor 23 Genetic testing Gene panel Hypophosphatemia Whole exome sequencing ABSTRACT Nutritional vitamin D defciency is the most frequent cause of rickets followed by genetic causes, that include entities like classic hypophosphatemic rickets (FGF23 related), Dent disease, Fanconi syndrome, renal tubular acidosis, and vitamin D dependent rickets. Hypophosphatemia is a feature in all these forms. The diagnosis relies on a combination of clinical, biochemical and radiological features, but genetic testing is required to confrm the diagnosis. We screened 66 patients with hypophosphatemic rickets referred to this center between May 2015 and July 2019 using whole exome sequencing (WES) in addition to the measurement of their intact serum fbroblast growth factor 23 (FGF23) levels. WES revealed 36 pathogenic and 28 likely pathogenic variants in 16 different genes (PHEX, FGF23, DMP1, ENPP1, CLCN5, CTNS, SLC2A2, GATM, SLC34A1, EHHADH, SLC4A1, ATP6V1B1, ATP6V0A4, CYP27B1, VDR and FGFR1) in 63 patients which helped differentiate between the various forms of hypophosphatemic rickets. Intact serum FGF23 levels were signifcantly higher in patients with variations in PHEX, FGF23, DMP1 or ENPP1 genes. The major genetic causes of rickets were classic hypophosphatemic rickets with elevated FGF23 levels, distal renal tubular acidosis, and vitamin D dependent rickets. Based on the present results, we propose a customized gene panel for targeted exome sequencing, which will be useful for confrming the diagnosis in most patients with hypophosphatemic rickets. 1. Introduction Nutritional rickets, due to defciency of vitamin D and/or calcium, is an important health problem in children in the developing world. In addition, several genetic causes of rickets have been reported, which are broadly classifed as phosphopenic or calcipenic. Phosphate defciency is the primary defect in phosphopenic rickets, and is chiefy caused by genetic disorders of renal phosphate handling leading to impaired tubular reabsorption. The important genetic causes of phosphopenic rickets are FGF23 related X-linked dominant, autosomal dominant and autosomal recessive hypophosphatemic rickets (Bitzan and Goodyer, 2019). Impaired proximal tubular reabsorption of phosphate is also seen in patients with Dent disease, renal Fanconi syndrome and renal tubular acidosis (RTA). On the other hand, calcipenic rickets consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D dependent rickets (VDDR) types 1A (VDDR1A), VDDR1B, VDDR2A, and VDDR2B. These patients show phosphate defciency secondary to its impaired gut absorption and hyperparathyroidism associated increased urinary losses (Jagtap et al., 2012;Molin et al., 2017). Hypophosphatemia, defned as blood levels of phosphate less than age-appropriate norms is therefore a feature of both types of rickets. Although the clinical diagnosis of hypophosphatemic rickets is based on clinical, radiological, and biochemical features, genetic testing helps confrm the diagnosis, and allows carrier detection and genetic coun- seling. It is important to distinguish the various causes of hypo- phosphatemic rickets (HR) since it has implications for defnitive therapy. There is limited data on the genetic basis of hypophosphatemic rickets from south Asia. Of the few genetic studies available, the ma- jority are in the form of case reports (Sethi et al., 2009; Kanakamani et al., 2010; Chandran et al., 2010; Gopalakrishnan et al., 2011; Ekbote et al., 2012; Dayal et al., 2013, 2014; Kehar et al., 2014; Ma et al., 2015; Bhardwaj et al., 2016; Shah et al., 2016; Amita et al., 2017; Divaker et al., 2018; Khandelwal et al., 2018; (Sandal et al., 2021). Using the approach of whole exome sequencing (WES), we prospectively exam- ined the etiology of hypophosphatemic rickets in consecutive patients referred to this tertiary care center, by testing for presence of disease-causing variations to enable molecular diagnosis and appro- priate therapy. * Corresponding author. Room No.1015, Department of Anatomy, First foor, Teaching Block, AIIMS, New Delhi, 110029, India.. E-mail addresses: arundhatisharma1@gmail.com, arundhatis@aiims.edu (A. Sharma). Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: www.elsevier.com/locate/ejmg https://doi.org/10.1016/j.ejmg.2022.104540 Received 1 December 2021; Received in revised form 5 April 2022; Accepted 9 June 2022