Novel Variant of AVPR2 Giving Rise to X-Linked Congenital Nephrogenic Diabetes Insipidus in a 7-Month-Old Danish Boy.

Patients affected with congenital nephrogenic diabetes insipidus (CNDI) have reduced ability to concentrate urine. Early diagnosis of CNDI is important to avoid recurrent episodes of severe dehydration. We present a Danish male suffering from typical symptoms and diagnosed with CNDI at the age of 7 months. Gene sequencing of this proband and his mother revealed a novel variant in the gene encoding the antidiuretic hormone receptor (AVPR2). The variant is a deletion of nucleotide c.151 in exon 2 of AVPR2 (GenBank NM_000054.4:c.151del). This 1bp deletion is predicted to cause a frameshift that results in tryptophan replacing valine at position 51 in AVPR2 and a premature stop codon three codons downstream (p.Val51Trpfs*3) likely resulting in faulty expression of the receptor. Identification of disease-causing variants such as the one described here contributes to precise diagnosis, especially in carriers and newborns, thus preventing the long-term physical and intellectual disability observed in some CNDI-patients.

Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis.

BACKGROUND: Pulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum of SLC34A2 has not been well investigated and it is not yet known whether a genotype-phenotype correlation exists. METHODS: We collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each variant, based on type and localisation within the protein. RESULTS: We identified eight novel allelic variants of SLC34A2 in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity. CONCLUSIONS: Our findings support a significant role for SLC34A2 in PAM and expand the variant spectrum of the disease. Thus, SLC34A2 variants were detected in all patients and eight novel allelic variants were discovered. An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations.

A novel variant in the SLC12A1 gene in two families with antenatal Bartter syndrome.

AIM: Bartter syndrome is an autosomal-recessive inherited disease in which patients present with hypokalaemia and metabolic alkalosis. We present two apparently nonrelated cases with antenatal Bartter syndrome type I, due to a novel variant in the SLC12A1 gene encoding the bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2 in the thick ascending limb of the loop of Henle. METHODS: Blood samples were received from the two cases and 19 of their relatives, and deoxyribonucleic acid was extracted. The coding regions of the SLC12A1 gene were amplified using polymerase chain reaction, followed by bidirectional direct deoxyribonucleic acid sequencing. RESULTS: Each affected child in the two families was homozygous for a novel inherited variant in the SLC12A1gene, c.1614T>A. The variant predicts a change from a tyrosine codon to a stop codon (p.Tyr538Ter). The two cases presented antenatally and at six months of age, respectively. CONCLUSION: The two cases were homozygous for the same variant in the SLC12A1 gene, but presented clinically at different ages. This could eventually be explained by the presence of other gene variants or environmental factors modifying the phenotypes. The phenotypes of the patients were similar to other patients with antenatal Bartter syndrome.