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.

MINAR2 is essential for normal hearing by regulating cholesterol localization in stereocilia in hair cells. MINAR2 knockout results in rapidly progressive sensorineural hearing loss (SNHL) in mice and zebrafish models. Recently, biallelic variants in MINAR2 have been reported to cause SNHL in four unrelated families with nonsyndromic severe to profound SNHL. Here we provide a second report of an additional family with SNHL. The index patient presented with nonsyndromic severe to profound SNHL. The family history was remarkable for a 20-year-old male sibling with nonsyndromic severe to profound SNHL. Both patients did not have any neurological involvement. Trio whole-exome sequencing of the index and his parents revealed a homozygous nonsense variant in MINAR2 (NM_001257308.2:c.319A>T; p.(Lys107*) in the index. Parents were heterozygous for the same variant. This variant introduces an early stop codon and probably results in a loss of function because of the predicted nonsense-mediated decay. Our study provides the first independent confirmation of the MINAR2-related SNHL.

Here we report a de novo heterozygous MED13 variant (c.2503C>T, p.Pro835Ser) in an infant presenting with infantile spasms, hypertrophic cardiomyopathy and hepatomegaly. Autopsy revealed mitochondrial abnormalities in cardiac and hepatic tissues, with reduced respiratory chain complex activity. This is the first case report linking a MED13 variant to systemic mitochondrial dysfunction, suggesting a novel pathogenic mechanism.