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.
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.
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.
