Journal of Medical Genetics最新文献

Despite the identification of many genes involved in developmental eye phenotypes, a large percentage of families lack genetic diagnoses, suggesting novel mechanisms remain to be discovered. Large deletions of 16p11.2, 3p14 or 19p13.11 regions involving transcription factors MAZ, FOXP1 and SIN3B, correspondingly, along with other genes, have been previously reported in individuals with neurodevelopmental and variable other features, including ocular coloboma and/or microphthalmia; recently, intragenic variants in FOXP1 and SIN3B have also been shown to cause neurodevelopmental phenotypes, with developmental eye defects reported in a small number of individuals with FOXP1 variants. Through exome sequencing analysis we identified novel splicing variants in MAZ and SIN3B, and a recurrent nonsense allele in FOXP1 in unrelated families affected with colobomatous microphthalmia, all with predicted loss-of-function effects; additionally, we report two new families with coloboma and 16p11.2 genomic deletions including MAZ, one de novo and another inherited from an affected parent. These findings provide further support for a role for FOXP1 in structural eye phenotypes, expanding its spectrum to include colobomatous microphthalmia, and suggest a role for MAZ and SIN3B in human eye development and disease.

Li-Fraumeni syndrome and Birt-Hogg-Dubé syndrome are distinct cancer predisposition syndromes caused by germline pathogenic variants (GPVs) in TP53 and FLCN, respectively. Multilocus inherited neoplasia alleles syndrome (MINAS) describes the co-occurrence of GPVs in two or more cancer predisposition genes. We present a unique case of a boy aged 16 years with multiple, very early onset atypical cutaneous fibrous histiocytomas (ACFHs), diagnosed with MINAS due to de novo TP53 and paternally inherited FLCN GPVs. This case is the first reported association of ACFH with germline TP53 and FLCN pathogenic variants. This paper highlights the importance of considering MINAS in patients with unusual tumour presentations. We discuss the clinical, histopathological and genetic findings, emphasising the need for comprehensive genetic testing and personalised surveillance in such cases.

Purpose and scope: The aim of this position statement is to provide recommendations aimed at Canadian reproductive care clinicians and genetics professionals regarding the use of reproductive carrier screening for autosomal recessive and X-linked recessive conditions.

Methods of statement development: A multidisciplinary expert group was assembled to review the existing literature on reproductive carrier screening for autosomal recessive and X-linked recessive conditions and make recommendations relevant to the Canadian context. The statement was circulated for comment to the membership of the Canadian College of Medical Geneticists (CCMG) and Canadian Association of Genetic Counsellors (CAGC), and multiple family physician reviewers. Feedback from these groups was incorporated, and the final position statement was approved by the CCMG Board of Directors on 5 December 2024 and the CAGC Board of Directors on 14 April 2025.

Results and conclusions: Routinely offered pan-ethnic reproductive carrier screening via a provincial or territorial programme is recommended for a limited panel of relatively common and severe childhood onset genetic conditions, based on Canadian experience with ethnicity-based testing: cystic fibrosis, fragile X syndrome, spinal muscular atrophy, haemoglobinopathies and founder mutations for Tay-Sachs disease, Canavan disease and familial dysautonomia. Provincial/territorial programmes must be developed to provide oversight, ensure appropriate resourcing and manage education and roll-out. Maintaining regional ethnicity-based screening programmes is also recommended, where relevant. Publicly funded population-level expanded carrier screening is not recommended at this time.

Background: Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients.

Methods: We investigated a large, well-phenotyped NF1 cohort.

Results: We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.

Conclusion: The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.

Background: Heterozygous PURA (Purine-rich element-binding protein A) variants cause PURA syndrome, a neurodevelopmental disorder characterised by hypotonia, seizures and intellectual disability. Previous studies have focused on the effect of the PURA variant in the cytoplasmic location, but nuclear mislocalisation remains to be explored.

Methods: We identified a de novo heterozygous frameshift variant (c.442del, p.L148Wfs*77) via trio whole-exome sequencing in one child suspected of PURA syndrome due to intellectual disability. Functional analyses included structural modelling, subcellular localisation assays, RNA-seq, CUT&Tag and DNA unwinding assays.

Results: The variant disrupts PURA repeats II-III, causing aberrant nuclear mislocalisation. RNA-seq revealed 688 differentially expressed genes enriched in neurodevelopmental pathways. CUT&Tag analysis revealed that PURA and Pol II exhibit enhanced binding at transcription start sites in cells expressing the variant, indicating dysregulated transcriptional engagement. Despite retained nucleic acid binding, the variant impaired DNA unwinding partly due to disrupted repeat III-mediated homodimerisation.

Conclusions: Nuclear mislocalisation of the PURA variant dysregulates transcriptional balance and impairs DNA unwinding, linking PURA's structural integrity to neurodevelopmental deficits. This highlights PURA's dual roles in cytoplasmic RNA regulation and nuclear transcription, providing mechanistic insights into PURA syndrome pathogenesis.

Rare variants in GRIA3, the gene encoding the GluA3 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs), are associated with defects in early brain development. Disease-causing variants are generally categorised as either loss of function (LoF) or gain of function (GoF) that appear to be linked to different symptoms. Here, we reported a de novo variant (N651D) that has mixed LoF and GoF in a female patient with a devastating developmental and epileptic encephalopathy, parkinsonism and cortical malformation. N651D is located in the M3 segment, which forms the filter pore of AMPAR tetramers. Interestingly, functional assays revealed that glutamate induced no currents in GluA3_N651D homomeric receptors, likely indicating an LoF effect. However, when co-expressed with the GluA2 subunit, the GluA2/A3_N651D heteromeric receptors showed slower deactivation and desensitisation curves, along with elevated non-desensitising steady-state currents, features typically observed in GoF variants. We speculate that variants with mixed LoF and GoF effects may lead to a more devastating phenotype compared with variants with GoF effects only.

Background: Hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) can be caused by SMAD4 pathogenic variants. SMAD4 is a common transcription factor of the BMP/TGFβ signalling pathway. In this study, we developed a cell-based functional assay to address the pathogenicity of SMAD4 variants identified in the French HHT cohort.

Methods: SMAD4 variants were generated by site-directed mutagenesis. A functional assay was developed in a cell line that does not express SMAD4, and the different SMAD4 variants were tested for their capacity to activate the BMP and TGFβ response using luciferase reporter assays.

Results: Twelve SMAD4 variants were identified and studied. We were able to develop a robust functional assay for these variants. All the expressed variants resulted in loss of function (LOF) in response to BMP9 or TGFβ1 stimulation. SMAD4 variants within the MH2 domain expressed SMAD4 mutated proteins that were unable to hetero-oligomerise with other SMADs, which could explain their LOF. Finally, we tested primary human endothelial cells isolated from patients with HHT carrying SMAD4 heterozygous pathogenic variants and observed that they behaved like the control cells at rest or when stimulated with BMP9.

Conclusion: We developed a SMAD4 functional assay that allows discrimination between benign and pathogenic SMAD4 variants. We demonstrated that the underlying molecular mechanism of this pathogenicity is due mostly to a loss of hetero-oligomerisation. This assay will be transferable to clinical genetic laboratories and will improve the diagnosis of patients with HHT-JPS.

Background: Fabry disease is a progressive, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to GLA variants. Females with Fabry disease often experience diagnostic delays and an underappreciated disease burden owing to their variable disease presentation and progression.

Methods: We conducted a post hoc analysis of all females from the clinical studies FACETS (NCT00925301) and ATTRACT (NCT01218659) and their open-label extensions, assessing baseline characteristics and long-term efficacy of migalastat regarding cardiac and renal function and Fabry-associated clinical events (FACEs).

Results: Overall, 60 females had a median migalastat exposure of 5.1 years. At baseline, the median age was 47 years with multiorgan involvement in 70.0% of females (≥2 organ systems: renal, cardiac, central nervous system, peripheral nervous system and gastrointestinal). At baseline, 21.7% of females had left ventricular hypertrophy (LVH). In multiorgan involvement and LVH subgroups, the median baseline estimated glomerular filtration rate (eGFR) was in chronic kidney disease stage 2. Annualised rate of change in left ventricular mass index remained below 1 g/m²/year regardless of LVH or eGFR category at baseline. Mean (SD) eGFR annualised change was -1.1 (2.8) mL/min/1.73 m² overall. Ten FACEs were reported in eight females, seven of whom had prior events. Seven FACEs were cardiac; the remaining three were cerebrovascular (all transient ischaemic attacks). The incidence of renal, cardiac and cerebrovascular events was 0, 24.9 and 10.7 events per 1000 patient-years, respectively.

Conclusion: These data show that females with Fabry disease experience considerable disease severity and burden and support the long-term efficacy of migalastat for the treatment of females.

Background: APC c.3920T>A; p.Ile1307Lys (I1307K), prevalent in individuals of Ashkenazi Jewish (AJ) origin, has been associated with a modestly increased colorectal cancer (CRC) risk. Clinical recommendations for I1307K heterozygotes vary across countries and expert groups, reflecting differences in population frequencies, modest risk estimates and limited data in non-AJ individuals.

Methods: We analysed UK Biobank data comprising 466 315 individuals (8944 with CRC), using genomic analysis to classify AJ and non-AJ ancestries.

Results: I1307K was identified in 7.1% of AJ and 0.08% of non-AJ white participants. No significant association with CRC was observed in AJ (OR: 0.71; 95% CI: 0.17 to 2.95) or non-AJ white individuals (OR: 1.05; 95% CI: 0.50 to 2.22). The previously established OR of 1.7-1.8 for AJ individuals lies within our 95% CI, indicating underpowered results due to limited CRC cases. No significant associations were detected for other cancers. Unbiased, adequately powered CRC case-control studies in non-AJ populations would require cohorts far larger than current resources for feasible analysis.

Conclusion: Clinical actionability of I1307K should prioritise risk stratification based on overall CRC risk and ancestry-dependent variant detection rates. However, management strategies need not differ by ancestry once a carrier is identified, as the biological impact of I1307K should be consistent across populations.

Purpose: The utility of genetic testing (GT) to guide cancer treatment, risk management and prevention has driven the demand for cancer genetic services. The global shortage of genetic counsellors (GCs) has led to the mainstreaming model. We evaluate the outcomes of the first GC-led service in Asia as a potential model for mainstreaming.

Methods: A retrospective review of patients managed by the service from 2013 to 2023 was conducted. Output data relevant to patient consultations, GT uptake and pathogenic variant carriers identified were extracted. A progress chart outlines the efforts made in addressing barriers, improving uptake and service delivery.

Results: Demand for GT has increased 18-fold. Uptake grew from 27% to an average of 81% from 2020, with no misconduct recorded. Carrier detection rate rose from 16% to 19-25% from 2015. The cost of GT has reduced significantly. Referral pathways for common hereditary cancer predisposition syndromes have been implemented. Support group events are held annually for carriers.

Conclusion: Our findings highlight the feasibility and success of a GC-led mainstreaming model that is safe and scalable. GCs are more time and cost-efficient than doctors in meeting GT demands while supporting carriers psychosocially. Expanding the GC workforce should be a priority in meeting the global demand for GT.