A Family with Gitelman Syndrome with Asymptomatic Phenotypes while Carrying Reported SLC12A3 Mutations.

Gitelman syndrome (GS) is an autosomal recessive disorder characterized by alkalosis, hypokalemia, and hypomagnesemia. Although hundreds of genetic variants associated with GS have been reported, many of them are categorized as of uncertain significance in ClinVar. Here, we describe a pediatric GS patient from a three-generation family whose mother and maternal grandmother were asymptomatic. The proband was a 16-year-old Japanese girl with muscle weakness and continuous hypokalemic metabolic alkalosis. The patient, her mother, and her maternal grandmother were compound heterozygous for, and each expressing a different combination of, previously reported SLC12A3variants in GS patients. The mother and the maternal grandmother had no symptoms related to GS, and blood gas tests showed that the blood potassium levels and venous pH were within normal limits; however, the venous blood HCO3- levels were slightly elevated. The phenotypic effect of missense mutations is difficult to evaluate, and accumulation of genotypic data with accurate phenotyping, including those of "healthy" and "asymptomatic" individuals in various ethnic populations, will improve the genetic diagnosis of GS.

Effect of filaggrin loss-of-function mutations on atopic dermatitis in young age: a longitudinal birth cohort study.

Atopic dermatitis (AD) is a chronic inflammatory skin disease, and skin barrier defects are often observed in patients with AD. So far, few association studies between FLG loss-of-function mutations and onset of AD in longitudinal studies of early childhood have been reported. In the present study, we aimed to investigate the effect of FLG loss-of-function mutations on the development of AD in a longitudinal birth cohort study. The status of AD diagnosis at each age until 6 years was collected from the Tokyo Children's Health, Illness, and Development (T-CHILD) study. We analyzed eight loss-of-function mutations in FLG in 712 participants. FLG loss-of-function mutations were significantly associated with AD onset in infancy (≤2 years) (P < 0.001, OR 3.54, 95% CI 1.88-6.65), but not with AD onset in childhood (≥3 years) (P = 0.981, OR 0.99, 95% CI 0.29-3.36), and none of the children in the present cohort who developed AD at 5 years of age or later carried FLG loss-of-function mutations. Our data support the notion that the effect of FLG loss-of-function mutations is prominent during a very early stage of life.