Scientific background:

Summary: The enzyme encoded by this gene activates vitamin D in the kidney. Calcidol resistant but Calcitriol remediable rickets result from inactivating mutation.

Gene: The gene (CYP27B1) is about 5kb in size. Its position is on chromosome 12 (12q14) in proximity to vitamin D receptor. It consists of 9 exons. All of them are translated.

Pathology: The gene product an enzyme that catalyses hydroxylation of vitamin D3 is almost exclusively located in the kidney mitochondria. The translation is regulated by negative feedback mechanism of calcitriol - the end product of vitamin D activation. The enzyme by itself is the key enzyme in vitamin D activation.

Clinical signs: The newborn child with defective enzyme is normal but the symptoms of rickets develop early in childhood within the first two years. Growth retardation, muscular weakness and bone deformities are often. Low plasma levels of calcitriol (1,25-dihydroxy vitamin D3) are typical. And it can not be elevated by oral vitamin D3 substitution. Lifelong substitution of calcitriol is an effective therapy.

Epidemiology: A complete deficiency is extremly rare. there are about 30 families known world wide. Almost all of them carry there own mutation.

Interpretation: The importance of genetic testing is confirmation of the diagnosis in cases with difficult differential diagnosis. The result is necessary for genetic counsulting. A genotype phenotype correlation is not available yet.

Test strategy: The necessity of genetic testing can be deduced from family counsultation and to provide prophylaxis to all family members without delay.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.
	research test	Method		Gene dosage measurements
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	Of the gene rearrangements, this method is useful to detect large deletions or duplications.

Literature: 

Kato S et al. (2002) Molecular genetics of vitamin D- dependent hereditary rickets.