Zimmermann-Laband syndrome is a rare, heterogeneous disorder characterized by gingival hypertrophy or fibromatosis, aplastic/hypoplastic nails, hypoplasia of the distal phalanges, hypertrichosis, various degrees of intellectual disability, and distinctive facial features. Three genes are considered causative for ZLS: KCNH1, KCNN3, and ATP6V1B2. We report on a pair of female concordant monozygotic twins, both carrying a novel pathogenic variant in the KCNN3 gene, identified using exome sequencing. Only six ZLS patients with the KCNN3 pathogenic variant have been reported so far. The twins show facial dysmorphism, hypoplastic distal phalanges, aplasia or hypoplasia of nails, and hypertrichosis. During infancy, they showed mild developmental delays, mainly speech. They successfully completed secondary school education and are socio-economically independent. Gingival overgrowth is absent in both individuals. Our patients exhibited an unusually mild phenotype compared to published cases, which is an important diagnostic finding for proper genetic counseling for Zimmermann-Laband syndrome patients and their families.

The human small-conductance Ca(2+)-activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family-based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co-morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case-control analysis that has demonstrated a significant over-representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co-morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive-compulsive disorder (OCD) co-morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN.

Familial and twin studies have suggested that anorexia nervosa (AN) is a multifactorial disorder with a substantial genetic contribution. The hSKCa3 potassium channel gene, which contains polymorphic CAG repeats in the coding region and is involved in the regulation of neuronal activity, may be a candidate gene for AN because alleles with longer repeats have been found to be associated with mental disorders. Forty Israeli AN family trios were genotyped for the hSKCa3 CAG repeat polymorphism using the haplotype relative risk (HRR) method. The distribution of alleles transmitted to the patients was found to be significantly different from that of the non-transmitted parental alleles, with the longer alleles being over-represented in the patients (Wilcoxon rank test, P = 0.008). The transmission disequilibrium test (TDT) revealed that longer (>19) repeat alleles were preferentially transmitted to AN patients (McNemar\'s chi(2) = 10.31, P = 0.0013). These results were corroborated by comparing the distribution of alleles between patients and healthy controls (Mann-Whitney test, P = 0.005). Our study suggests that the longer repeat alleles of the hSKCa3 gene may contribute to the genetic susceptibility to AN.