**Background:** Rickets is a disorder of growing bone caused by deficiency or defective metabolism of calcium, phosphorus, or vitamin D. While nutritional deficiency is the most common cause worldwide, hereditary forms account for about 13% of cases and are classified into vitamin-D-dependent rickets (VDDR) and hypophosphatemic rickets (HR). Overlap in clinical presentation with nutritional rickets poses diagnostic challenges, making molecular diagnosis crucial for appropriate management. This study aimed to characterize the phenotypic and genotypic spectrum of monogenic rickets in 10 Indian families.
**Methods:** Ten unrelated individuals (P1–P10) with suspected hereditary rickets were recruited. Detailed history, clinical photographs, radiographs, and biochemical investigations were obtained. Exome sequencing was performed on probands using various platforms and capture kits. Variant analysis followed an in-house strategy with pathogenicity assessment based on population databases (gnomAD, ExAC), in-house exome data (2155 exomes), in silico prediction tools (MutationTaster, REVEL, M-CAP, SIFT, Splice AI), and ACMG-AMP guidelines.
**Key Results:** Eleven disease-causing variants were identified, including five previously reported and six novel variants. The variants were distributed across six genetic forms of rickets:
- **VDDR1A (CYP27B1):** Three individuals (P1, P2, P3) had homozygous or compound heterozygous variants. P1 had a novel missense variant c.974C>T (p.Thr325Met) and severe early-onset disease (age 4 months). P2 had a known duplication c.1319_1325dup (p.Phe443Profs*24). P3 had compound heterozygous variants c.1376G>A (p.Arg459His) and c.1319_1325dup.
- **VDDR1B (CYP2R1):** One individual (P4) had two novel compound heterozygous variants: c.595C>T (p.Arg199*) and c.1330G>C (p.Gly444Arg).
- **VDDR2A (VDR):** One individual (P5) had a known homozygous missense variant c.1171C>T (p.Arg391Cys) and presented with severe rickets and alopecia.
- **X-linked dominant hypophosphatemic rickets (PHEX):** Three individuals (P6, P7, P8) had heterozygous variants: c.1586_1586+1del (splice-site), c.1482+5G>C (splice-site), and c.58C>T (p.Arg20*), respectively.
- **Hypophosphatemic rickets with hypercalciuria (SLC34A3):** One individual (P9) had a novel homozygous splice-site variant c.1336-11_1336-1del.
- **Fanconi–Bickel syndrome (SLC2A2):** One individual (P10) had a novel homozygous missense variant c.589G>C (p.Val197Leu).
Clinical features included wrist widening (9/10), genu varum (7/10), genu valgum (4/10), and radiological findings such as osteopenia (9/10), frayed metaphyses (9/10), and bowing of lower limbs (8/10). Consanguinity was present in 7 families. Biochemical profiles were consistent with each disorder (e.g., low calcium and phosphate with elevated ALP in VDDR1A; low phosphate with elevated ALP in XLDHR).
**Clinical Implications:** This study expands the mutation spectrum of monogenic rickets by adding six novel variants. It underscores the importance of exome sequencing in diagnosing hereditary rickets, especially when nutritional causes are excluded or treatment fails. Early molecular diagnosis can guide targeted therapy (e.g., calcitriol for VDDR1A, phosphate supplements for XLDHR) and improve clinical outcomes. The overlap with conditions like osteogenesis imperfecta (as in P10) highlights the need for genetic testing to avoid misdiagnosis.