Exome Sequencing in Monogenic Forms of Rickets

Abstract

Objective To understand the phenotypic and genotypic spectrum of genetic forms of rickets in 10 families. Methods Detailed clinical, radiographic, and biochemical evaluation of 10 families with phenotypes suggestive of a genetic cause of rickets was performed. Molecular testing using exome sequencing aided in the diagnosis of six different forms of known genetic causes. Results Eleven disease-causing variants including five previously reported variants (CYP27B1:c.1319_1325dup, p.(Phe443Profs*24), VDR:c.1171C>T, p.(Arg391Cys), PHEX: c.1586_1586+1del, PHEX: c.1482+5G>C, PHEX: c.58C>T, p.(Arg20*)) and six novel variants (CYP27B1:c.974C>T, p.(Thr325Met), CYP27B1: c.1376G>A, p.(Arg459His), CYP2R1: c.595C>T, p.(Arg199*), CYP2R1:c.1330G>C, p.(Gly444Arg),SLC34A3:c.1336-11_1336-1del, SLC2A2: c.589G>C, p.(Val197Leu)) in the genes known to cause monogenic rickets were identified. Conclusion The authors hereby report a case series of individuals from India with a molecular diagnosis of rickets and provide the literature review which would help in enhancing the clinical and molecular profile for rapid and differential diagnosis of rickets.

Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity

“…In this context, several studies demonstrated that mutations in three CYP genes ( CYP7A1 , CYP7B1 , and CYP27A1 ) affect bile acid synthesis and cholesterol homeostasis, with different phenotypes leading to metabolic pathologies [ 46 , 47 , 48 , 49 , 50 , 51 ]. Defects in CYPs 2R1 and 27B1, involved in the conversion of vitamin D into its physiologically active form, are genetic causes of rickets [ 52 , 53 , 54 , 55 ]. Deficiency in the retinoic acid-metabolizing enzymes from the CYP26 family is associated with skeletal and craniofacial anomalies [ 56 , 57 ].…”

Rickets is Not Always Nutritional!

“…Depending upon the type of inheritance, genetic rickets occurs due to mono or biallelic variants in either of 20 genes (such as PHEX, FGF23, DMP1, ENPP1, SLC34A3, SLC34A1, SLC9A3R1, CLCN5, OCRL1, FGFR1, FAM20C for hypophosphatemic rickets and CYP27B1, CYP2R1, CYP3A4, VDR for vitamin D-dependent rickets). In this issue of the journal, Jacob et al have studied 10 families with monogenic rickets at different ages with varying phenotypic severity across various genetic etiologies [1].…”

“…Although inactivating biallelic variants found in the DNA binding domain (DBD) implicate a severe phenotype in autosomal recessive vitamin D-dependent rickets type 2A (VDDR2A) [6], the genotype-phenotype correlation is not elusive for genetic rickets. Jacob et al found a homozygous Arg391Cys variant in the C-terminal ligand-binding domain (LBD) yet with a severe phenotype due to poor vitamin D responsive element (VDRE) binding in vivo and reduced transactivation [1].…”