Journal of Medical Genetics最新文献

Background: Tau-tubulin kinase 1 (TTBK1) is a neuron-enriched kinase implicated in τ phosphorylation and neurodegeneration. Human phenotypes associated with constitutional TTBK1 variants remain undefined.

Methods: Two siblings with a severe neurodevelopmental phenotype were assessed using quartet exome sequencing, segregation analysis and standardised clinical and neuroimaging evaluations.

Results: Both children exhibited profound global developmental delay, non-ambulation, axial hypotonia with lower-limb spasticity and proportionate postnatal growth failure with microcephaly. Epilepsy was present in the older sibling. Brain MRI showed a thin brainstem and corpus callosum, periventricular T2 hyperintensities and mild cerebellar atrophy in the older sibling and external hydrocephalus in the younger. Exome sequencing identified a homozygous frameshift variant in TTBK1 (NM_032538.3:c.1899del; p.Thr634Argfs*39) that segregated with the disease. The variant was absent from population databases and predicted to cause loss-of-function. According to the American College of Medical Genetics and Genomics criteria, it fulfils PVS1 and PM2_P.

Conclusion: We report the two siblings with a neurodevelopmental disorder due to a biallelic TTBK1 loss-of-function variant, establishing TTBK1 as critical for human neurodevelopment. Together with preclinical data, these findings underscore its role in motor and cognitive circuits. Additional cases and functional studies will be essential to delineate the clinical spectrum and mechanistic basis of TTBK1 deficiency.

Background: Chromosome 19 is the most gene-dense chromosome in the human genome, with a high frequency of segmental duplications that predispose it to genomic rearrangements. While deletions of chromosome 19 have been associated with various clinical conditions, duplications remain poorly characterised. Here, we report three cases involving 19p13.11 duplication and describe the associated clinical phenotype.

Methods: We describe three unrelated individuals with microduplications at 19p13.11 identified either via clinical whole-exome sequencing or chromosomal microarray. The probands underwent detailed clinical genetic evaluations, and CNVs were confirmed with parental testing when available. Sequencing reads were aligned to the GRCh37/hg19 human genome build.

Results: All three probands exhibited neurodevelopmental delays, attention-deficit/hyperactivity disorder and speech delay. Additional overlapping features included joint hypermobility, short stature and craniofacial anomalies. Patient-specific manifestations included haematological abnormalities, musculoskeletal asymmetries and cardiac findings. Duplicated regions spanned 1.2-1.6 Mb and encompassed 41-49 protein-coding genes. Patients 2 and 3 have CNVs that overlap 76% with those of Patient 1. Several genes have predicted high triplosensitivity scores and are associated with autosomal dominant neurodevelopmental and skeletal disorders. Patient 1, with the largest duplication, had more extensive systemic involvement, likely reflecting the broader gene dosage effect.

Conclusion: This is the first comprehensive clinical and molecular characterisation of 19p13.11 duplications, suggesting a recurring multisystem phenotype driven by gene dosage sensitivity. These findings support the inclusion of 19p13.11 duplications in diagnostic evaluations for neurodevelopmental and multisystem disorders.

Background: Desmin (DES) is a major intermediate filament protein involved in the structural integrity and function of striated muscles. Pathogenic mutations in DES are predominantly missense variants, causing isolated cardiomyopathy and combinations of myopathy and cardiomyopathy. In-frame insertions are very rare and usually classified as variants of uncertain significance or likely pathogenic due to limited predictive and/or experimental evidence.

Methods: This study describes a novel heterozygous in-frame insertion in exon 6 of DES (RefSeq NM_001927.4:c.1059_1061dup) identified in an Argentine family with myofibrillar myopathy (MFM). This mutation results in the duplication of a glutamic acid residue at position 353 (NP_001918.3:p.(Glu353dup)), in the 2B subdomain of the central rod domain. Clinical, computational and functional analyses were performed to study the pathogenicity of this variant.

Results: Clinically, the index patient exhibited hallmark MFM features, including progressive muscle weakness, atrophy and fatty muscle replacement. In silico analyses of molecular dynamics revealed that p.Glu353dup alters DES dimer assembly by stabilising an aberrant coiled-coil conformation, a mechanism not previously proposed for DES mutations. Functional studies in HEK293T cells and C2C12 myocytes suggested that the p.Glu353dup variant induces aberrant DES aggregation, confirming its detrimental effect on filament organisation.

Conclusion: These findings are consistent with the idea that p.Glu353dup is a pathogenic variant, supported by clinical studies, in silico protein modelling and functional evidence, highlighting the impact of in-frame insertions on DES filament homeostasis. By providing computational and experimental evidence, this study expands our understanding of desminopathies and offers new perspectives for pathogenicity assessment of uncertain DES variants.

Duchenne muscular dystrophy (DMD) is a severe X-linked myopathy characterised by progressive skeletal and cardiac muscle degeneration, loss of ambulation, respiratory failure and premature mortality. Although corticosteroids and gene therapies have improved disease management, they are limited by significant side effects, mutation specificity and delivery challenges, underscoring the need for an alternative or an adjunctive strategy. Emerging evidence identifies autophagy dysregulation as a critical secondary pathological mechanism in DMD, contributing to impaired clearance of damaged organelles and toxic protein aggregates, exacerbating muscle atrophy and fibrosis.This review aims to acknowledge current insights into autophagy regulation in healthy muscle and its disruption in DMD, explore its crosstalk with key pathological pathways such as nuclear factor kappa B signalling, mitochondrial dysfunction and endoplasmic reticulum stress and critically evaluate emerging therapeutic strategies targeting autophagy.Autophagy, a fundamental cellular recycling process, is suppressed in DMD by hyperactivation of the Akt-mTOR pathway and dysregulated calcium homeostasis. This leads to mitochondrial dysfunction, oxidative stress and activation of inflammatory cascades. Recent preclinical studies highlight the therapeutic potential of pharmacological and dietary autophagy modulators, including rapamycin, 5-aminoimidazole-4-carboxamide ribonucleotide, low protein diets, SRT2104 and Givinostat, which improve autophagic flux, restore mitochondrial integrity and attenuate fibrosis. Lifestyle interventions and combinatorial approaches further underscore the importance of integrating multimodal strategies.Further research should focus on longitudinal studies to optimise therapeutic timing, validate dynamic biomarkers (LC-II, p62, miRNAs) and leverage artificial intelligence with multiomics integration for precision therapies. Targeting autophagy and its interconnected pathways holds promise for transforming DMD management and improving patient outcomes.

Background: Biallelic pathogenic variants in PNKP are associated with microcephaly and early-onset seizures (MCSZ), ataxia with oculomotor apraxia type 4 and Charcot-Marie-Tooth disease type 2B2.

Methods: We describe the clinical and neuroimaging features of 27 new patients with PNKP variants. All patients presented with early-onset seizures, congenital microcephaly and intellectual disability. In addition, we compared our results with data in the literature.

Results: Twenty-five patients presented with the classic MCSZ phenotype, while two showed a more severe clinical phenotype. The brain imaging features of the 25 patients varied significantly, but widening of the frontal lobe gyri with frontal hypoplasia and prominent cerebellar folia (consistent with atrophy) could point to PNKP-related microcephaly . In contrast, the two patients with severe phenotype showed additional brain MRI features of white matter loss and pontocerebellar hypoplasia fulfilling the criteria of microlissencephaly. Exome sequencing identified seven different PNKP variants, including two novel ones. The c.1253_1269dup p.(Thr424GlyfsTer49) and c.1381_1383dup p.(Asn461dup) variants, each was recurrent in 10 patients (37%), while the c.1381_1383del p.(Asn461del) variant was recurrent in four patients (14.8%). Haplotype analysis confirmed that the p.Asn461dup variant has a founder effect in our population. No genotype-phenotype correlation was observed in our cohort.

Conclusion: Our results provide 'microlissencephaly' as an emerging distinct phenotype linked to PNKP variants. As such, PNKP variants could be associated with four overlapping subgroups that lie along a unifying phenotypic continuum.

Deleterious variants in the BRSK2 gene, which encodes a serine/threonine kinase crucial for neuronal polarisation and brain development, have recently been linked to the pathogenesis of autism spectrum disorder (ASD). However, comprehensive clinical descriptions of individuals with pathogenic BRSK2 variants remain limited, and the molecular and cellular consequences of these mutations are poorly understood. This case report provides a detailed clinical, cognitive and molecular characterisation of a male patient with ASD harbouring a de novo BRSK2 frameshift variant, who developed catatonia, developmental regression and cognitive decline during early adolescence. To assess the functional impact of the variant, induced pluripotent stem cells (iPSCs) and iPSC-derived neural organoids were generated from the patient. Molecular analyses revealed a significant reduction in BRSK2 transcript and protein levels. Sequencing of BRSK2 mRNA showed exclusive expression from the wild-type allele, consistent with degradation of the mutant transcript via nonsense-mediated decay. These findings broaden the mutational and phenotypic spectrum associated with BRSK2-related neurodevelopmental disorders and provide functional evidence supporting the pathogenicity of the identified variant. Furthermore, this report demonstrates the role of BRSK2 in complex neuropsychiatric features-such as catatonia and cognitive deterioration, which remain underreported in the existing literature-and emphasises the importance of longitudinal cognitive and behavioural monitoring in individuals with BRSK2 mutations.

Background: Pathogenic gain-of-function or dominant-negative effect missense variations in ACTB are associated with a neurodevelopmental disorder characterised by intellectual disability (ID), seizures, sensorineural hearing loss, cerebral, renal and ocular abnormalities and dysmorphic features (Baraitser-Winter cerebrofrontofacial syndrome). ACTB encodes beta-actin, a highly conserved protein involved in cell motility, structure and integrity. Deletions including ACTB, and, more rarely, single-nucleotide loss-of-function variants in ACTB have been described in patients with a distinct phenotype including developmental delay, ID, microcephaly, growth restriction, cardiac and renal abnormalities and dysmorphic features.

Methods: We collected 14 individuals and 1 fetus carrying a heterozygous deletion including ACTB, and 4 individuals with a heterozygous truncating variant. Genotypic and phenotypic data were analysed. Furthermore, a comprehensive review of all cases reported to date was also undertaken.

Results: Twelve out of 17 individuals presented with ID, and 3 out of 17 with learning disabilities. Speech delay and behavioural abnormalities were observed in 15 out of 17 and 12 out of 17 individuals, respectively, motor delay in 9 out of 17 and growth restriction in 9 out of 18. Most of the individuals (13/18) had recognisable dysmorphic features. 11 anomalies were de novo, except for 1 deletion inherited from the mother. The size of the deletion varied from 125 kb to 1.6 Mb and could result from a fork stalling and template switching.

Conclusion: This study allowed us to better characterise the phenotype associated with the haploinsufficiency of ACTB, underlying the high prevalence of neurodevelopmental disorders (ID, speech and motor delay, behavioural abnormalities) and growth restriction in this recognisable syndrome.

Background: Familial exudative vitreoretinopathy (FEVR) is an inherited eye disease characterised by the incomplete development of the retinal vasculature. Over 10 genes have been associated with FEVR, but there are still a substantial number of genetically unsolved cases. The aim of this study was to analyse whole genome sequencing (WGS) data from the FEVR cases in the Genomics England (GEL) 100 000 genomes project to identify the causative variants.

Methods: WGS was performed by GEL and accessed within the GEL Research Environment. FEVR cases were identified using LabKey and candidate variants were extracted using the 'gene-variant workflow' and 'CNV/SV workflow' and by using BCFtools in unfiltered VCF files.

Results: Fifty-nine FEVR probands were submitted to GEL. We found six novel and eight previously reported pathogenic variants in six genes known to underlie FEVR (TSPAN12, LRP5, FZD4, CTNNB1, KIF11 and NDP), as well as structural variants in TSPAN12 and KIF11. These accounted for 15/59 (25.4%) of FEVR cases. We also found candidate heterozygous variants in CTNND1 in three unsolved FEVR cases. Expanding the list of genes examined to include all genes reported to be mutated in ocular disorders likely solved a further four cases, indicating that these individuals may be misclassified as FEVR in GEL.

Conclusion: By performing bespoke reanalysis of the FEVR GEL cohort, this study has highlighted additional heterozygous variants in CTNND1 in FEVR cases and increased the diagnostic yield from 20% solved by the GEL analysis pipeline to 37% (22/59), but the majority of FEVR cases remain without a molecular diagnosis.

Background: Mitochondrial diseases are genetic disorders arising from pathogenic variants in nuclear or mitochondrial DNA (mtDNA) characterised by respiratory chain dysfunction. Clinical manifestations are diverse, and treatment is mostly symptomatic. Mitochondria are maternally inherited, but new reproductive technologies may prevent the transmission of pathogenic mtDNA. We decided to investigate the pregnancies of women with the m.3243A>G mtDNA variant.

Methods: 16 women with m.3243A>G were included in this retrospective, observational cohort study. Medical records were screened for pregnancies managed at Oulu University Hospital (Oulu, Finland) during the years 1960-2020. Main outcomes were obstetric complications as well as maternal and neonatal morbidity. All eligible pregnancies (n=38) were reviewed for the course of pregnancy and delivery as well as maternal and neonatal health.

Results: The median of maternal m.3243A>G load in muscle or buccal epithelium was 59% (range 30-76%). There were 30 deliveries and 31 born children. Among singleton pregnancies, gestational diabetes was present in seven (24%), gestational hypertension or pre-eclampsia in three (10%) and preterm delivery in two (7%). Mean birth weight was 3537 g (1020-5310 g), with a z-score of 0.80±1.37 for girls and 0.77±1.05 for boys. Seven newborns (12%) were treated in the neonatal intensive care unit.

Conclusion: Women harbouring m.3243A>G may have an elevated risk for obstetric complications, such as gestational diabetes and gestational hypertension. Their babies may have an elevated risk of preterm birth and need for intensive care. Pregnancies of women with m.3243A>G should be followed carefully.