Microcephaly with or without chorioretinopathy, lymphedema or mental retardation is a rare KIF11-related disorder. Here we report the case of a patient with microcephaly, lymphedema, nystagmus and familial exudative vitreoretinopathy carrying a novel de novo KIF11 nonsense variant (NM_004523.4:p.Glu123Ter), which is considered pathogenic. This case expands the phenotypic range of KIF11 pathogenic variants and highlights the importance of early ophthalmological evaluation, genetic counseling and family assessment.

Personalized thiopurine therapy is among the most established examples of pharmacogenomics translated into clinical practice. Variants in TPMT (rs1800462, rs1800460, rs1142345) and NUDT15 (rs116855232) are recognized clinical predictors of thiopurine efficacy and toxicity. Additional variants in genes such as PACSIN2 (rs2413739), ITPA (rs1127354) and MTHFR (rs1801133 and rs1801131), also contribute to variability in drug response. Here we characterize the frequency of the pharmacogenetic variants involved in thiopurine metabolism in a healthy population of Kosovo. We genotyped 299 healthy blood donors for polymorphisms. Among TPMT variant alleles, TPMT*3A was observed at a frequency of 2.0%, and the TPMT*3C at 0.1%. Notably, the MTHFR 677T variant (rs1801133) was significantly more frequent in the Kosovo population (49.8%) compared with the global and European frequencies. The minor allele frequency of MTHFR rs1801131 was 27.4%. Minor allele frequencies for PACSIN2 rs2413739 and ITPA rs1127354 variants were 48.8% and 4.0%, respectively. Sequencing of NUDT15 revealed six variants, with rs116855232 present at frequency of 0.8%. These findings provide important insights into the pharmacogenomic profile of the Kosovo population and support the implementation of pre-emptive genotyping to improve the safety and efficacy of thiopurine therapy in the region.

Array-based comparative genomic hybridization for a boy, his mother and his half-sister with etiology-unknown nonsyndromic short stature identified a hitherto unreported heterozygous ~1.5-Mb deletion at 16q24.2-q24.3. Whole-exome sequencing detected no pathogenic variants. Our results, in conjunction with previous reports of cases with similar deletions, indicate that the 16q24.2-q24.3 region provides a platform for submicroscopic deletions and possibly contains a gene(s) or regulatory elements involved in skeletal growth.

Recently, the Tohoku Medical Megabank Organization released whole-genome allele frequencies of single-nucleotide variants and indels from approximately 60,000 individuals from the general Japanese population in the Tohoku region (60KJPN). Here we analyzed the 60KJPN dataset for BRCA1/BRCA2 variants and compared them with the previous version, 54KJPN, to ascertain the frequency of hereditary breast and ovarian cancers in the general Japanese population. We hope that these results will contribute to strategies for cancer prevention.

Here we report a Chinese infant with hypophosphatasia (HPP) carrying alkaline phosphatase (ALPL) gene mutations. Genetic analysis of the patient’s ALPL gene revealed a maternally inherited canonical splice-site variant (c.997+1G>T; pathogenic; PVS1 + PM2 + PP4) and a paternally inherited missense variant (c.1405C>T, p.His469Tyr; reclassified as pathogenic; PP4 + PM2 + PP3). Both variants have previously been reported in gnomAD with very low frequency in Chinese infants.

An episignature is a genome-wide DNA methylation pattern that is specific to each syndrome or etiologic gene. Episignature analysis helps to diagnose patients with variants of uncertain significance (VUS), but this requires positive methylation datasets from patients with a definitive diagnosis. Here we provide methylation datasets of Rubinstein–Taybi syndrome at the individual patient level, which have not been published before. This dataset increases the likelihood of determining the function of the VUS.

Fontaine progeroid syndrome (FPS) is a rare condition characterized by abnormalities in SLC25A24. Some instances of FPS have been reported to be fatal early in life. Here we present the first case of mitochondrial disease diagnosed with FPS in Japan. The diagnosis was based on the presence of the heterozygous known pathogenic variant of SLC25A24, NM_013386.5: c.649C>T and decreased activity of mitochondrial respiratory chain enzyme activity.

Hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) is a rare autosomal recessive neurological disorder that affects fewer than 1 in 1,000,000 individuals worldwide and is characterized by neonatal hypotonia, respiratory and feeding difficulties, impaired motor development and autonomic abnormalities with highly variable age of onset and severity. Here we report a novel homozygous DST variant in association with HSAN-VI in two Pakistani siblings.

Here we report an 18-year-old male patient with bilateral ectopia lentis and biallelic CPAMD8 variants (NM_015692.5:c.[2801delG];[4552C>T]; NP_056507.3:p.[(Gly934GlufsTer64)];[(Gln1518Ter)]). He exhibited previously unreported extraocular features, including a slender build, scoliosis, arachnodactyly and positive thumb sign and wrist sign, which is reminiscent of Marfan syndrome. These findings may suggest that CPAMD8-related disorder is a syndromic condition associated with extraocular systemic features similar to those seen in Marfan syndrome.