Haploinsufficiency of NKX2-1 is likely to contribute to developmental delay involving 14q13 microdeletions.

Nucleotide variations or deletions in the NK2 homeobox 1 gene (NKX2-1), located at 14q13.3, lead to symptoms associated with the brain, lungs, and thyroid, and the combination of these phenotypes is clinically recognized as the brain-lung-thyroid syndrome. Many types of nucleotide variants of NKX2-1 have been identified, and phenotypic variability has been reported. Chromosomal deletions involving NKX2-1 have also been reported; however, phenotypic differences between patients with nucleotide variants of NKX2-1 and patients with chromosomal deletions involving NKX2-1 have not been well established. Recently, we identified seven patients with 14q13 microdeletions involving the NKX2-1. Most patients exhibited developmental delay. This inquiry arises regarding the potential existence of haploinsufficiency effects beyond those attributed to NKX2-1 within the 14q13 microdeletion. However, a literature review has shown that developmental delay is not rare in patients with nucleotide alterations in NKX2-1. Rather, motor function impairment may have affected the total developmental assessment, and the haploinsufficiency of genes contiguous to NKX2-1 is unlikely to contribute to developmental delay.

Variant spectrum of PIEZO1 and KCNN4 in Japanese patients with dehydrated hereditary stomatocytosis.

Hereditary stomatocytosis (HSt) is a type of congenital hemolytic anemia caused by abnormally increased cation permeability of erythrocyte membranes. Dehydrated HSt (DHSt) is the most common subtype of HSt and is diagnosed based on clinical and laboratory findings related to erythrocytes. PIEZO1 and KCNN4 have been recognized as causative genes, and many related variants have been reported. We analyzed the genomic background of 23 patients from 20 Japanese families suspected of having DHSt using a target capture sequence and identified pathogenic/likely pathogenic variants of PIEZO1 or KCNN4 in 12 families.

Clinical and genetic diagnosis of thirteen Japanese patients with hereditary spherocytosis.

Hereditary spherocytosis is the most frequent cause of hereditary hemolytic anemia and is classified into five subtypes (SPH1-5) according to OMIM. Because the clinical and laboratory features of patients with SPH1-5 are variable, it is difficult to classify these patients into the five subtypes based only on these features. We performed target capture sequencing in 51 patients with hemolytic anemia associated with/without morphological abnormalities in red blood cells. Thirteen variants were identified in five hereditary spherocytosis-related genes (six in ANK1 [SPH1]; four in SPTB [SPH2]; and one in each of SPTA1 [SPH3], SLC4A1 [SPH4], and EPB42 [SPH5]). Among these variants, seven were novel. The distribution pattern of the variants was different from that reported previously in Japan but similar to those reported in other Asian countries. Comprehensive genomic analysis would be useful and recommended, especially for patients without a detailed family history and those receiving frequent blood transfusions due to chronic hemolytic anemia.