Novel genes contributing to rickets

Rickets is a common childhood condition characterized by improper bone mineralization, resulting in deformities and growth impediments. It is caused by deficiencies or metabolic issues related to vitamin D, phosphorus, or calcium. 

Diagnostic tests involving various biochemical markers assist in categorizing and treating rickets, with genetic assessment often necessary for optimal management. Genetic causes can be either monogenic rickets or linked to inherited metabolic disorders. The genetic basis may involve variants in specific genes, leading to vitamin D-dependent or hypophosphatemic rickets. Recent research by Jacob et al. examined 10 families with monogenic rickets, revealing diverse genetic etiologies and phenotypic severities.

Historically, genetic contributions to rickets were estimated at 13%, but advancements in genomic studies, like next-generation sequencing, have identified novel genes, expanding our understanding. Examples include SGK3, linked to autosomal dominant hypophosphatemic rickets, and autosomal dominant renal Fanconi syndrome due to partial GATM deficiency. Digenic inheritance, involving multiple gene variants, has also been reported in certain cases. While inactivating variants in the DNA binding domain indicate severe phenotypes in some types of rickets, the overall genotype-phenotype correlation remains complex. Jacob et al. discovered a homozygous Arg391Cys variant associated with a severe phenotype, emphasizing the importance of understanding genetic factors.

Given the clinical similarities between nutritional and genetic rickets, identifying clues such as – consanguinity, family history, and poor response to vitamin D therapy is crucial. When these indicators are present, genetic testing through exome sequencing becomes essential for early diagnosis, targeted therapy initiation, and genetic counseling.

Source: S S, GuptaN. Indian J Pediatr.2023;90:1169–1170.