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.

Keywords: Exome sequencing; Hypophosphatemic rickets; Rickets; Vitamin-D-dependent rickets.

Fig. 1

Radiographic profile of an individual with vitamin-D-dependent rickets type I. P1 (age: 4 y) shows delayed tooth eruption at 8 y 9 mo (a), delayed carpal ossification (b), metaphyseal dysplasia at the ends of long bones (c–e): small epiphyses at the knee (c), bending of long bones (c, d), and small capital femoral epiphysis (e). The radiographic appearance was affected by his treatment

Fig. 2

Radiographs of an individual with vitamin-D-dependent rickets type IIA. P5 (age 4 y) shows severe osteopenia, small epiphyses at the knee, irregular metaphyses, bending of the fibula (a), dorsal–lumbar kyphosis (b), and cupping of radius and ulna (c and d)

Fig. 3

Lower limb radiograph of P6 with X-linked hypophosphatemic rickets (age 22 y). Bowing of long bones, and osteopenia with frayed metaphyses are seen (a)

Fig. 4

Radiographic profile of P10 (age 8 y) with Fanconi–Bickel syndrome. Multiple sites of fracture and osteopenia are seen in her upper and lower limbs (a–c)