Loss-of-function variants in TRMT10A are known to cause a rare autosomal recessive disorder primarily characterized by microcephaly, short stature, and impaired glucose metabolism. However, the extent of phenotypic variability and the factors influencing clinical heterogeneity remain poorly understood. Here, we describe two individuals harboring distinct biallelic loss-of-function variants in TRMT10A who exhibited divergent developmental phenotypes. The first patient, a 34-year-old man with a homozygous early frameshift variant, presented with preserved cognitive function and previously unreported multisystem features, including male infertility, high-grade myopia, bilateral sensorineural hearing loss, and tetralogy of Fallot. In contrast, the second patient, a 3-year-old boy with a homozygous deletion involving exons 6-7, demonstrated early-onset developmental delay, epilepsy, congenital heart disease, and neonatal hypoglycemia. Transcript-level analyses supported the predicted effects of both variants on TRMT10A transcripts. These findings suggest phenotypic variability associated with TRMT10A loss-of-function variants. Notably, the frameshift variant identified in the adult patient has previously been reported in association with a more typical neurodevelopmental phenotype, whereas our patient exhibited preserved cognitive function. This observation supports variable expressivity and suggests that additional factors may contribute to clinical heterogeneity.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetically and epigenetically complex disorder in which the comprehensive characterization of the D4Z4 repeat array remains challenging. We applied Oxford Nanopore long-read sequencing (ONT-LRS) to three patients with FSHD, one unaffected control, and a trio family to simultaneously characterize D4Z4 repeat size, haplotype, DNA methylation, and genomic structure. Results were validated by Southern blotting, single-molecule optical mapping and bisulfite sequencing. ONT-LRS enabled integrated characterization of D4Z4 repeat size, haplotype, single-molecule methylation, and genomic structure. Single-molecule methylation profiling revealed reduced and heterogeneous methylation across individual D4Z4 repeats. Reference-guided haplotype-resolved assembly generated consensus sequences spanning the D4Z4 array and flanking regions. By applying the assembled consensus sequences, we identified a deletion outside the D4Z4 region and precisely localized its breakpoint in the trio family. These findings demonstrate that ONT-LRS enables comprehensive genetic and epigenetic characterization of FSHD in a single assay, providing a potentially valuable approach for molecular diagnosis and facilitating investigation of genotype-phenotype relationships. 1. ONT-LRS enables direct measurement of D4Z4 repeat and repeat-level methylation, with high concordance to SB, SMOM, and bisulfite sequencing. 2. ONT-LRS is applied to generate the first consensus D4Z4 sequence in Chinese FSHD patients and to achieve accurate breakpoint mapping.

Loss-of-function variants in the melanocortin 1 receptor (MC1R) gene are a well-established cause of red hair in European populations. However, the genetic spectrum and phenotypic effects of MC1R variants in East Asians remain poorly defined, as red hair is exceedingly rare in this population. To characterize the clinical and genetic features of MC1R-associated red hair and hypopigmentation in Chinese pediatric patients and to expand the genotypic spectrum of MC1R in East Asian populations, four unrelated Chinese children with red or reddish-brown hair underwent comprehensive dermatologic and ophthalmologic assessments and whole-exome sequencing. All MC1R variants were confirmed by Sanger sequencing, and parental samples were analyzed to determine inheritance. In silico prediction tools and structural modeling were used to assess potential pathogenicity and protein-level impact. Seven MC1R variants were identified, including three novel variants: one frameshift (p.Ala28Thrfs*23) and two missense variants (p.Pro295Leu and p.Ser90Asn). Patients carrying compound heterozygous variants showed more pronounced hypopigmentation with bright red hair, whereas the heterozygous carrier of p.Thr157Ile exhibited a milder phenotype. Structural modeling suggested that these variants likely affect transmembrane or intracellular regions of the receptor, potentially altering protein conformation and impairing signaling function. No pathogenic variants in classic oculocutaneous albinism genes were detected. This study expands the genotypic spectrum of MC1R and demonstrates that MC1R deficiency alone can result in an "albinism-like" red hair phenotype in East Asian populations. These findings support including MC1R in the differential diagnosis for Asian patients with unexplained red hair and mild hypopigmentation.

In the clinical management of hereditary cancer syndromes, risk assessment is needed not only for affected patients but also for their blood relatives. In the families of Lynch syndrome (LS) patients, cascade testing is performed to identify those who carry germline pathogenic variants (GPVs) of mismatch repair genes and to enable the clinical surveillance of cancer-prone organs in relatives with GPVs. To date, the uptake of cascade testing has not been fully reported, and only a limited number of studies have analyzed barriers to its implementation. This retrospective study analyzed the uptake of cascade testing in relatives of Japanese LS probands and clarified factors that promote it. The study included 56 LS probands and 162 first-degree relatives (FDRs). Clinicodemographic data were collected from medical records, and univariate and multivariate analyses compared those who did and did not undergo cascade testing. Fifty-two (32.1%) FDRs of LS probands underwent cascade testing. Independent predictors of cascade testing uptake were the attendance of a family member at the proband's genetic counseling session (odds ratio [OR]: 3.6), female sex of the proband (OR: 2.9), and female sex (OR: 2.2). The cascade testing uptake in this study was comparable to or lower than rates reported in other countries. Encouraging family members to attend genetic counseling with the proband may improve cascade testing uptake in LS families. Further prospective studies are needed to clarify the reasons for accepting or declining cascade testing, including an evaluation of intrafamilial communication processes.

The narrow-sense heritability of a trait refers to the proportion of phenotypic variance attributable to additive genetic effects and provides a predictive upper bound for linear polygenic scores. Performance benchmarking in the context of continuous traits is generally performed using the coefficient of determination (R[2]). Several definitions of R[2] exist, however, and here we demonstrate that the correlation-based R[2] is the appropriate formulation for the specific task of heritability benchmarking. For non-linear and machine-learning-based polygenic scores, the more relevant performance ceiling is the broad-sense heritability. However, the uncritical use of R[2] for the assessment of non-linear models has long been cautioned against. We show that correlation-based R[2] can still be meaningfully interpreted as the proportion of phenotypic variance recoverable from a model's predictions, even when generated through non-linear means. We therefore highlight the importance of reporting correlation-based R[2] when benchmarking both traditional and machine-learning-based genomic prediction models against trait heritability.

Riddle syndrome is a rare autosomal recessive disorder caused by RNF168 mutations, characterized by radiosensitivity, immunodeficiency, and dysmorphic features. We reported the first Asian family cluster involving a homozygous RNF168 c.91T>C (p.Cys31Arg) mutation in three siblings. The proband, a 37-year-old female, presented with severe restrictive lung disease, achalasia, and progressive respiratory failure requiring mechanical ventilation. Two sisters exhibited milder phenotypes with dysmorphic features and elevated alpha-fetoprotein. Whole-genome sequencing confirmed the mutation in all affected individuals. The cluster highlighted phenotypic heterogeneities, including neuromuscular and gastrointestinal involvement not previously reported in Riddle syndrome. These findings underscored genetic evaluation for RNF168 mutations in patients with unexplained recurrent infections, elevated alpha-fetoprotein and esophageal motility disorders. Early recognition remained crucial for genetic counseling and clinical managements.

DNAJB2 encodes an HSP40 co‑chaperone involved in protein quality control and maintenance of neuronal proteostasis. Pathogenic variants in this gene, typically inherited in an autosomal recessive manner, cause hereditary motor neuropathy (HMN), Charcot-Marie-Tooth disease (CMT), and other neuromuscular disorders. In this study, we report two unrelated families harboring two distinct splice-site variants within the same intron of DNAJB2: one affecting the acceptor site and the other the donor site, identified in patients presenting with HMN and CMT, respectively. We also performed a systematic review of previously reported variants to further investigate phenotypic variabilities and likely genotype-phenotype correlations. Whole‑exome sequencing (WES) was performed for probands with clinical diagnosis of hereditary neuropathy. Identified variants were confirmed by Sanger sequencing, and co‑segregation analysis was conducted within the families. A systematic review was performed following PRISMA 2020 guidelines using PubMed, Scopus, and Google Scholar databases (January 2000-May 2026). WES identified a known variant, c.446‑1 G > C, in one proband and a novel one, c.445+1del, in another. Clinically, the first patient showed an HMN phenotype, whereas the second presented with an axonal CMT (CMT2). In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state. Our study expands the mutational spectrums of this gene, and the systematic evaluation of DNAJB2-related cases demonstrates the marked clinical heterogeneity but not a significant genotype-phenotype correlation.

A pathogenic GGC repeat expansion in zinc finger homeobox 3 (ZFHX3), encoding a pure polyglycine (polyG) tract, causes spinocerebellar ataxia type 4 (SCA4). Intermediate expansions of other SCA loci have been implicated in amyotrophic lateral sclerosis (ALS), while repeat motif composition is recognised to influence pathogenicity in neurodegenerative diseases. Given the genetic pleiotropy between ALS and SCA, we evaluated whether ZFHX3 GGC expansions are associated with ALS and characterised repeat motif composition. ZFHX3 GGC repeat sizes were genotyped using ExpansionHunter in short-read whole-genome sequencing data from ALS cases and healthy controls of European ancestry. Repeat sizes were visually inspected using REViewer, and motif configurations were manually derived from a subset. Receiver operating characteristic analysis and Youden's J statistic identified a candidate repeat size threshold. Logistic regression tested associations of repeat length and motif composition with ALS, while regression models assessed clinical phenotypes. Across 5785 ALS cases and 7982 controls, no association was observed between ZFHX3 expansions and ALS risk. Longer alleles showed a nominal association with later disease onset, however this did not remain significant after Bonferroni correction. Among 802 ALS cases and 800 controls, 50 distinct motif compositions were identified, including 11 encoding pure polyG tracts characteristic of pathogenic SCA4 expansions; none were associated with ALS. Although no association with ALS was observed, this study established the dynamic nature of ZFHX3 repeat motif composition and configuration. Variation within and between repeat sizes, including pure polyG repeats, supports consideration of motif composition alongside allele length when evaluating neurodegenerative disease risk.

Only 14 individuals have been thus far described with GlyT1 encephalopathy due to biallelic variants in the SLC6A9 gene and the phenotypic picture is incomplete. Early mortality has been high, with only two known to survive into infancy. We report a 27-year-old individual who, to our knowledge, is the eldest person described with this ultra-rare disorder and who brings new phenotypic insights alongside potential prognosis for younger individuals. He is compound heterozygous for two novel SLC6A9 variants. He shares many unifying clinical features, including neonatal hypotonia with later hypertonicity, respiratory failure, exaggerated startle and arthrogryposis. Clinical course stabilised after early childhood. Perampanel was of significant benefit for the exaggerated startle. Significant visual loss is unexplained. It may relate to the essential role of GlyT1 in retinal amacrine cells, although this mechanism remains speculative.

Non-coding GGC repeat expansions in NOTCH2NLC and AAGGG repeat expansions in RFC1 have been implicated in NIID and CANVAS, respectively. Both disorders classically present with peripheral neuropathy as an initial manifestation. This study aimed to investigate the prevalence of short tandem repeat (STR) expansions in NOTCH2NLC and RFC1 among patients with genetically undiagnosed inherited peripheral neuropathy (IPN). In this cohort study, we screened 103 such patients for STR expansions using repeat-primed PCR and fragment analysis. Clinical, electrophysiological, and skin histopathological features of patients were comprehensively analyzed. Additionally, a systematic literature review was conducted to summarize all published NOTCH2NLC-related IPN cases. Four patients with IPN (3.9%, 4/103) were found to have heterozygous GGC repeat expansions in NOTCH2NLC. Two patients harboring biallelic AAGGG repeat expansions in RFC1 exhibited predominantly sensory axonal neuropathy. A total of 107 patients in seven reports were identified. The most prevalent clinical features were impaired motor function (66/86, 76.7%), followed by sensory abnormalities, tremor, and muscle atrophy. The size of the expanded GGC repeats ranged from 68 to 517. Sporadic NIID cases presented with later onset and milder features compared to familial cases. Radiological and cognitive manifestations correlated with onset age but not with repeat size. Our results indicate that STR expansions account for 5.8% (6/103) of genetically undiagnosed IPN cases in our cohort. This study broadens the clinical spectrum of NOTCH2NLC and RFC1 repeat expansions and highlights the importance of screening for STR expansions among genetically undefined IPN patients.

Osteoporosis and fractures are major health concerns. We developed and validated a polygenic score (PGS) for quantitative ultrasound (QUS)-defined osteoporosis risk in Japanese individuals using heel QUS-derived T-scores. Genome-wide association study summary statistics from up to 10,794 participants in the Tohoku Medical Megabank Community-Based Cohort identified genome-wide significant loci, including MBL2, TMEM135, and WNT16. PGS models were constructed and evaluated using independent datasets for model selection (n = 1419) and validation (n = 8711). Adding the PGS to age and sex yielded only modest improvements in discrimination, whereas PGS quintiles supported genetic risk stratification. Compared with the intermediate group, individuals in the lowest PGS quintile had higher odds of the outcome (1.22, 95% confidence interval [CI]: 1.07-1.40), whereas those in the highest quintile had lower odds (0.85, 95% CI: 0.74-0.98). During prospective follow-up (mean 3.5 years), a similar gradient was observed, with higher incidence rate ratios in the lowest quintile (1.42, 95% CI: 1.17-1.73) and lower incidence rate ratios in the highest quintile (0.70, 95% CI: 0.54-0.89). No statistically significant interaction between age and PGS was observed, and age-T-score regression analyses showed no differences in age-related T-score decline across genetic risk groups. However, analyses in young adults (20-44 years) and extrapolation to age 20 suggested lower bone status around peak bone mass in individuals at high genetic risk for QUS-defined osteoporosis. These findings suggest that a Japanese-specific PGS may help identify individuals at elevated genetic risk earlier in adulthood.

Okur-Chung neurodevelopmental syndrome (OCNDS; OMIM #617062) is an ultra-rare autosomal dominant disorder caused by heterozygous CSNK2A1 variants encoding CK2α; although the CSNK2A1 Foundation registry lists more than 350 diagnosed individuals worldwide, individual-level phenotypic data have been published for far fewer, and reports from Türkiye remain scarce. We retrospectively studied nine unrelated Turkish probands (4 F/5 M; 11 months to 23 years) from nine medical genetics centers across four geographic regions of Türkiye, diagnosed by exome sequencing (ES; n = 8) or chromosomal microarray (n = 1). A PRISMA 2020-compliant systematic review (inception-April 2026) provided an individual-level comparator pooled with our cohort (n = 61). Six distinct CSNK2A1 alterations were identified: the recurrent p.(Lys198Arg) p + 1 loop hotspot in 4/9 probands (44.4%); novel/rare p.(Arg195Gln) and p.(Asp156His) missense changes; two nonsense variants (p.(Tyr182Ter), p.(Arg333Ter)); and one ~537 kb heterozygous 20p13 contiguous deletion (arr[GRCh37] 20p13(61568_598427)x1). This proband also represents 20p13 deletion syndrome; previously reported cases of that entity were compared with our cohort. Core OCNDS features (developmental delay, intellectual disability, hypotonia, dysmorphism, behavioral disturbance) occurred at frequencies comparable to those in the pooled literature. Adult-onset obesity with type 2 diabetes (2/9) and hypogonadism (2/9), both essentially unreported in the predominantly pediatric pooled literature, were observed in two adolescent/young-adult males (one with p.(Lys198Arg), one with the 20p13 deletion). This series consolidates Lys198 as a recurrent hotspot across ethnically diverse cohorts, extends the structural-variant spectrum with the first Turkish CSNK2A1 contiguous-gene deletion, and supports adult-onset metabolic-reproductive complications as under-recognized OCNDS features. Systematic adolescent and adult metabolic-endocrine surveillance is recommended regardless of variant class.

Pathogenic variants in HNRNPK are associated with autosomal dominant Au-Kline syndrome (AKS, Au-Kline-Okamoto syndrome, OMIM #616580). This syndrome is characterized by developmental delay and intellectual disability, hypotonia, and distinctive facial features. Despite the use of whole-genome sequencing (WGS) as a powerful diagnostic tool, we nearly dismissed a novel intronic variant (NM_031263.4(HNRNPK):c.214-55 T > A) affecting HNRNPK splicing and function. Although commonly used bioinformatic splice prediction tools, including SpliceAI and PDIVAS, yielded inconclusive results, Face2Gene analysis indicated a high phenotypic similarity to AKS. Characteristic facial features described by Choufani et al. [1] supported the clinical diagnosis of AKS. Subsequent functional studies demonstrated aberrant splicing with intron retention, and DNA methylation profiling revealed a positive HNRNPK-specific episignature. These insights and the de novo status support an evaluation as likely pathogenic. This case report supports the relevance of facial analysis and comprehensive variant validation strategies, particularly for deep intronic variants with ambiguous in silico splicing predictions.

We report a 28-year-old infertile male presenting with markedly reduced progressive sperm motility and severe morphological abnormalities (normal morphology rate: 1%), accompanied by primary ciliary dyskinesia (PCD)-like symptoms, including chronic rhinitis, adolescent nasal polypectomy, and persistent rhinorrhea. Transmission electron microscopy (TEM) revealed ultrastructural defects involving the sperm head, nucleus, and flagellar axoneme. Whole-exome sequencing (WES) identified two novel compound heterozygous nonsense variants in the GAS8 gene: c.280 G > T (p.Glu94Ter) and c.382 C > T (p.Gln128Ter). Based on these findings, testicular sperm aspiration (TESA) combined with intracytoplasmic sperm injection (ICSI) was performed, resulting in a biochemical pregnancy. This case expands the mutational and phenotypic spectrum of GAS8 and provides additional clinical evidence relevant to genetic diagnosis, genetic counseling, and assisted reproductive management of male infertility accompanied by PCD-like symptoms.

Transposon-like human element (THE1) repeats are classified as part of the ERVL (endogenous retrovirus-like) -MaLR family and were previously thought to be remnants derived from retroviral infections in the germ cells of ancient primates. At present, at least 60,561 THE1 repeats have been mapped in the human genome, and they are divided into four subfamilies: THE1A, THE1B, THE1C, and THE1D. Although these repeats are largely silenced in somatic cells through multiple mechanisms, some of them are known to influence gene functions and genomic structures, particularly under disease conditions. Recently, we happened to identify the CIR1 driven from THE1B in the individuals with sarcoid myopathy (SM), which is characterized by the non-caseating granulomatous inflammation recognized in skeletal muscles biopsy. Retrotrans-genomics based on the COFFEE method showed that various THE1B fusion transcripts (THE1B/FTs) and retrotransposon-associated genomic dynamics in muscle of SM, including (1) splicing of THE1B to neighborhood exons, (2) expression of THE1B associated long noncoding RNAs in the intergenic regions, (3) ectopic expression of tissue specific transcripts driven by THE1B in SM, and (4) identification of a read through transcript, SIRPB1-SIRPD. Seven of eight THE1B/FTs downregulated by tofacitinib in cutaneous sarcoidosis were confined to the granuloma associated macrophage in sarcoidosis. The remaining transcript, SMFT4 exhibited stronger expression in mesenchymal stem cells. In addition, ectopic co-expression of canonical and LINE1 and THE1A-exonizing IL23R transcripts were identified in SM. This directory of THE1B/FTs in SM may serve as a fundamental molecular basis for understanding the pathogenesis of sarcoidosis.