Journal of Medical Genetics最新文献

Background: Molecular genetic diagnoses are critical to prevention and treatment of inherited polyposis and colorectal cancer. 19 genes responsible for these conditions are known, but many severely affected patients and families remain unsolved. Cryptic intronic variants that alter splicing of these genes and incomplete characterisation of recessive predisposition contribute to these diagnostic gaps.

Methods: Adaptive sampling long-read DNA sequencing targeted to 19 colon cancer genes, paired with direct long-read RNA whole-transcriptome sequencing, was undertaken for four patients referred for deficiency of mismatch repair proteins and/or familial polyposis, for whom multigene panel testing yielded negative or uncertain germline results.

Results: Genetic diagnoses were obtained for all four patients. Each patient carried a cryptic intronic germline variant in a different colon cancer gene. The variants abrogated splicing by various mechanisms, all leading to loss of gene function. Patient 1 was heterozygous for intronic insertion into MSH2 of an Alu element, leading to extension of transcription into the affected intron and a stop. Patient 2 was heterozygous for deep intronic insertion into APC of a Long Interspersed Nuclear Element (LINE), creating a pseudoexon and a stop. Patient 3 was compound heterozygous at MLH3, including a cryptic intronic substitution leading to exon skipping and a stop. Patient 4 was compound heterozygous at MUTYH, including a deep intronic deletion yielding an extremely short intron and transcriptional loss of an exon encoding a critical protein domain.

Conclusion: Paired long-read DNA and RNA sequencing can enhance diagnostic yield through detection of cryptic intronic variants that impact cancer predisposition.

Li-Fraumeni syndrome (LFS) is a high-risk hereditary cancer predisposition syndrome affecting 1 in 5000 individuals. Current standard of care in adults includes annual whole-body MRI (WB-MRI) and MRI brain (MRB) surveillance to enable early cancer detection. We performed a retrospective single-centre study of adults with TP53 pathogenic germline variants or proven somatic mosaicism undergoing annual WB-MRI surveillance between January 2012 and January 2024, and MRB surveillance between August 2017 and January 2024. 325 WB-MRI scans were performed in 75 individuals. 17 cancers were diagnosed in 16 individuals. Nine out of 17 cancers were WB-MRI detected (7/9 had stage 1/2 disease). Benign incidental findings were identified in 89/325 (27.4%) of WB-MRI scans, prompting 53 additional investigations. As a stand-alone surveillance tool, WB-MRI demonstrated a pan-cohort specificity of 95.5%, negative predictive value of 97.4% and sensitivity of 42.9%. 32 individuals underwent 53 MRB scans detecting one cancer. We report the findings from the longest and largest single-centre experience of WB-MRI surveillance for cancer early detection in adults with LFS, demonstrating a high and acceptable level of cancer exclusion but modest sensitivity with WB-MRI prompting a significant number of additional investigations.

Background: Biallelic pathogenic TULP3 variants have been associated with a novel ciliopathy named hepatorenocardiac degenerative fibrosis, which is characterised by hepatic fibrosis in childhood or early adulthood, fibrocystic kidney disease later in life and hypertrophic cardiomyopathy in the elderly. Its genotype and phenotype spectrum are largely unknown.

Methods: Patients presenting with liver diseases between 2015 and 2023 at The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, and carrying biallelic rare variants of TULP3 were studied. Variants of uncertain significance were evaluated for pathogenicity in vitro.

Results: Two unrelated children carrying biallelic rare variants in TULP3 were identified. Patient 1 had variants c.666T>G, p. (Tyr222Ter) and c.1291G>C, p. (Gly431Arg). She initially presented with neonatal cholestasis, which rapidly progressed to liver fibrosis, with liver transplantation at 2 years of age. She also had intellectual disability and attention deficit hyperactivity disorder. Patient 2 had variants c.73C>T, p. (Gln25Ter) and c.1211T>G, p. (Met404Arg). He was found to have liver fibrosis, portal hypertension and abnormal cranial imaging at the age of 7.5 years. Both non-sense variants, c.73C>T and c.666T>G, were predicted to result in non-sense-mediated mRNA decay. Missense variant Met404Arg abolished TULP3 expression, while Gly431Arg reduced the localisation of TULP3 in cilia. Both Met404Arg and Gly431Arg impaired ciliogenesis and the trafficking of ARL13B and INPP5E into cilia.

Conclusion: Severe neonatal cholestasis and/or neurological symptoms may be novel manifestations of disease in patients harbouring compound heterozygous TULP3 variants. Missense variants in TULP3 may impair ciliogenesis or normal cilia function by abolishing the normal expression or localisation of cilia proteins.

Background: Approximately 1-3% of patients with Huntington disease (HD) present with HD-like phenotype but test negative for the HD gene, suggesting other causes.

Methods: This study presents the first case of Huntington disease-like 1 (HDL-1) in a Chinese family and summarises the clinical features of previously reported HDL-1 cases and patients with octapeptide repeat insertion (OPRI) mutations.

Results: The proband, a 36-year-old woman, presented with progressive involuntary movements, bradykinesia, cognitive decline and personality changes over 6 years, worsening over the past year. Similar manifestations were noted in her grandmother, father and aunt. Genetic testing revealed an 8-OPRI mutation in PRNP, confirming HDL-1. Neuroimaging showed increased T2-Fluid Attenuated Inversion Recovery (FLAIR) signals in the hippocampi and atrophic changes in the frontal and parietal lobes. Electroencephalography indicated a slowed background rhythm. A 1-year follow-up visit showed amelioration of choreic movements. A literature review identified five families with HDL-1, with age of onset ranging from 18 years to 54 years and disease duration from 3 months to over 20 years. Common manifestations included movement disorders, dementia, personality changes and heterogeneous symptoms such as epilepsy. Imaging showed ventricular enlargement and diffuse brain atrophy, primarily affecting the basal ganglia, frontal lobes, temporal lobes and cerebellum. Pathologically, prion protein antibody staining was positive, although spongiform changes were not prominent.

Conclusion: These cases highlight the importance of considering familial prion diseases in patients with hereditary chorea and a negative HD gene test. Careful attention to treatment and follow-up can provide valuable insights for managing these patients.

Background: Variants in the Kinesin-family member 5A (KIF5A) gene are associated with a range of motor diseases, and a strong correlation between the protein domains (motor, stalk and tail) and the clinical phenotype has been proposed. However, several studies have reported exceptions contributing to a complex genotype-phenotype correlation in recent years. Further studies are needed to improve our knowledge about the prevalence of KIF5A variants and their genotype-phenotype correlation.

Methods: 390 patients (220 hereditary spastic paraplegia, 80 Charcot-Marie-Tooth disease type 2 and 90 amyotrophic lateral sclerosis) have been selected for next-generation sequencing Clinical Exome.

Results: Five patients have been found to carry causative variants in the KIF5A gene. Of these, three are familiar cases, and two are sporadic. Segregation analysis was performed on the familiar probands. The five patients with pathogenic variants represent 4% of the studied population, and the clinical and genetic analysis of these five families allowed us to examine different scenarios.Some of these data support the hypothesis of a complex correlation between domains and disease.

Conclusion: These data confirm the complex genotype-phenotype correlation, both in terms of clinical heterogeneity associated with a specific domain and variability within the members of the same family, but also suggest a strong genotype-phenotype correlation, both intrafamiliar and interfamiliar, produced by a few variants.

Background: Nanophthalmos is a rare ocular condition characterised by a significantly short axial length (AL) and high hyperopia, often associated with various complications. This study aims to provide a comprehensive analysis of the clinical and genetic features of nanophthalmos in a large Chinese cohort.

Methods: A total of 105 patients from unrelated families diagnosed with nanophthalmos were included. Genetic testing was performed using whole exome sequencing to identify variants in genes associated with the condition. Clinical features, including demographic data, the presence of accompanying clinical findings and various ocular parameters, were compared across different genetic groups.

Results: Whole exome sequencing revealed variants in four key genes: PRSS56, MFRP, MYRF and TMEM98, with a detection rate of 71.43%. Autosomal recessive genes (PRSS56 and MFRP) were associated with shorter AL, higher hyperopia, shallower vitreous chamber depth and steeper corneal curvatures (larger K1 and K2). In contrast, autosomal dominant genes (MYRF and TMEM98) were linked to earlier onset of glaucoma and a higher incidence of multiple ciliary body cysts. In the patients carrying variants in PRSS56 and MFRP, biallelic variants were associated with more severe phenotypes, including more extreme ocular parameters and increased risks of specific complications, compared with monoallelic variants.

Conclusion: This study represents the largest cohort of nanophthalmos patients reported to date, expanding the genetic and clinical understanding of the condition. It identifies novel variants and provides valuable insights into genotype-phenotype correlations, highlighting the impact of genetic variation on the disease severity and associated complications of nanophthalmos.

Background: A substantial fraction of hereditary hearing loss (HL) remains unexplained by known HL genes. Tbx2 is a developmental transcription factor critical for inner ear hair cell differentiation in mice, while its pathogenic role in genetic HL in humans has yet to be documented. Here, we identified heterozygous TBX2 frameshift variants that cause human HL, establishing a previously unrecognised genetic link.

Methods: Linkage analysis combined with whole-genome sequencing (WGS) was applied to identify the causative gene in two unrelated Chinese families with autosomal dominant progressive sensorineural HL (SNHL) accompanied by incomplete penetrance nystagmus. Functional evaluation of TBX2 variants was performed through protein expression, localisation and transcriptional activity analysis in vitro, phenotypic analysis and mechanism study in knockout and knock-in mice model in vivo.

Results: Linkage analysis in Family 1 mapped SNHL to chr17q23.2 (maximum logarithm of odds=3.01), WGS identified two rare heterozygous TBX2 variants (c.977delA, p.Asp326Alafs*42 and c.987delC, p.Ala330Argfs*38) each segregating with the phenotype in a separate family. Affected individuals exhibited isolated auditory and oculomotor phenotypes, without additional syndromic features seen in previously described TBX2-associated disorders. In vitro assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity. In vivo, heterozygous Tbx2 knockout mice (Tbx2^+/- ) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.

Conclusion: These findings establish TBX2 as a novel gene for syndromic HL, defining a new autosomal dominant disorder characterised by progressive HL with variable nystagmus. This discovery expands the spectrum of T-box transcription factor disorders and informs molecular diagnosis and genetic counselling in hereditary HL.

Growth retardation, alopecia, pseudoanodontia and optic atrophy (GAPO) syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in the ANTXR1 gene. While significant progress has been made in understanding its molecular basis, no systematic description of the clinical phenotype is available.We conducted a comprehensive review of 105 cases reported in the available literature since the first description of GAPO syndrome in 1947. We summarise here the current understanding of the clinical phenotype and the genetic basis of the condition.Our findings point out the multisystemic nature of GAPO syndrome, primarily featuring skeletal, dermatological and ophthalmological manifestations. The condition is caused by the biallelic loss-of-function of ANTXR1 Histological findings throughout the reported cases underscore the critical role of excessive extracellular matrix deposition in the pathogenesis of GAPO syndrome. The evidence gathered suggests ANTXR1 as an important regulator of extracellular matrix homeostasis.This study highlights the clinical and molecular spectrum of GAPO syndrome. Early recognition, multidisciplinary care and genetic counselling are essential for improving patient outcomes. Future studies should focus on targeted therapies addressing extracellular matrix dysregulation.