Journal of Medical Genetics最新文献

Background: Previous reports of distal deletions in chromosome 10q in patients have described distinct facial features combined with other neurodevelopmental abnormalities, including intellectual disability. However, the association of interstitial deletions in chromosome 10q with global developmental delay, musculoskeletal abnormalities, and dysmorphic features has not been previously reported.

Methods: Genetic testing using whole exome sequencing (WES) was performed on three patients with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Sequencing reads were aligned to the human genome build GRCh37/UCSC hg19 and analysed for both sequence and copy number variants.

Results: WES identified similar interstitial deletions in the 10q21.1q21.3 locus in all three patients. The deleted region includes online Mendelian inheritance in man (OMIM)-annotated genes with clinical significance, such as ANK3 (*600465), JMJD1C (*604503), EGR2 (*129010), BICC1 (*614295), ZNF365 (*607818) and TFAM (*600438). Deletion of this region is considered pathogenic and is implicated in the aetiology of the clinical phenotypes observed in these patients.

Conclusions: This is the first report associating interstitial deletions in the 10q21.1q21.3 locus with neurodevelopmental delay, musculoskeletal abnormalities and dysmorphic features. Our findings highlight the clinical significance of this deleted region and suggest possible mechanisms underlying the observed pathological phenotypes.

Background: Pathogenic variants in the DMD gene are associated with dystrophinopathy including Duchenne and Becker muscular dystrophy (DMD/BMD). Targeted DMD gene, gene panels, exomes and genome sequencing have advanced genetic diagnostics, yet some cases remain elusive.

Methods: We performed total RNA sequencing (RNAseq) on muscle biopsy from 13 male patients with a clinical diagnosis of DMD/BMD. Splice aberration events are evaluated using the Integrative Genomics Viewers. Targeted DNA sequencing result was used/re-analysed to confirm complex rearrangement events identified.

Results: RNAseq identified aberration splicing or expression events in the DMD gene of 12 cases. Splice-altering intronic single nucleotide variant events including c.7309+5G>T, c.7309+5G>A, c.3276+1G>A and c.3603+820G>T were identified in four cases. Splice-altering events were also detected in one case with small indel c.94-38_94del and two cases with intragenic deletions (exons 51-52 and 45-47 deletions). Furthermore, complex DNA rearrangements inducing aberration splicing/expression events were identified in five cases involving exons 44-45, 55-56, 2-79, 45-79 or 68-79, which were concordant with their DNA sequencing reanalysis results. Some cases with exon deletions have presented non-canonical transcripts expression. The RNAseq result showing aberrant splicing/expression in different exon regions in most of these cases corresponded with their immunohistochemical dystrophin staining results and/or clinical symptoms.

Conclusion: Our data demonstrated RNAseq is a powerful tool to provide functional data for DMD splice aberration events, especially when integrating with immunohistochemical testing and DNA sequencing, for elucidating the pathogenicity of DMD variants and achieving a precise genetic diagnosis in patients with DMD/BMD clinical presentation but without definitive diagnoses after routine genetic testing.

Lateralised overgrowth (LO) is characterised by the asymmetric increase in the size of any part of the body exceeding 10% compared with the unaffected contralateral one. LO is a key feature in various syndromic overgrowth disorders, such as Beckwith-Wiedemann spectrum and PIK3CA-related overgrowth spectrum (PROS). However, it can also present as isolated (ILO). Defining the aetiology of LO is critical due to the clinical implications and management strategies required for each condition. This report presents two patients who were followed up throughout childhood for ILO and were ultimately diagnosed with PROS through molecular analysis on DNA extracted from a skin biopsy, revealing the PIK3CA:c.263G>A (p.Arg88Gln) variant at a high variant allele frequency. This variant has been described in association with macrocephaly-capillary malformation syndrome but not with ILO. In conclusion, this is the first report of patients harbouring the (p.Arg88Gln) variant with a diagnosis of ILO, thus, highlighting the importance of considering ILO within the PROS and underscoring the necessity for somatic DNA testing. An early and accurate molecular diagnosis is crucial for guiding appropriate clinical management in order to ensure access to targeted therapies, emphasising the need for further research to refine diagnostic criteria and testing recommendations for ILO.

Background and aims: Neurofibromatosis-Noonan syndrome (NFNS) is an extremely rare genetic entity combining the clinical phenotype of two conditions: neurofibromatosis type 1 syndrome (NF1) and Noonan syndrome (NS). Nevertheless, many inconsistencies reside in our understanding of this condition, mainly its clinical features and genetic background. Through this systematic review, we aim to shed light on the epidemiological features, the broad clinical spectrum, the underlying genetic defects and the associated comorbidities of NFNS.

Methods: Medline, Scopus and Google Scholar were searched for publications on the clinical and genetic features of patients with NFNS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed and the study protocol was registered in PROSPERO.

Results: Of 951 records screened, 42 were eligible. The mean age at diagnosis was 14.7 years ranging from 0 to 69 years. As for the circumstance of discovery of NFNS, it was dominated by family investigation followed by neurofibromas, facial dysmorphia and short stature (SS). Prematurity was noted in 40.9% of cases. The hallmark features of NFNS at diagnosis were 'café au lait' macules, typical facial dysmorphia of NS, postnatal SS, pectus abnormalities, broad neck and lentigines. Macrocephaly, scoliosis and cardiopathies occurred in 26%, 42.4% and 36.9% of cases, respectively. Tumours were found in 18.4% of cases. As for the genetic foundation of NFNS, NF1 gene mutations were depicted in 87.5% of individuals.

Conclusions: Based on our findings, we emphasise on the importance of searching for NS features in patients with NF1 since the prognosis, comorbidities and consequently management could be altered.

Prospero registration number: 42024522238.

In 1997, the Journal of Medical Genetics published our paper on the spectrum of clinical features associated with interstitial chromosome 22q11 deletions. This copy number variation is associated with an extraordinary range of clinical features, which led initially to its association with several diagnostic labels. Since 1997 work on clinical and basic science aspects of the syndrome and the genes reduced to hemizygosity have provided a wealth of information pertaining to both best practice care and underlying biology. It is recognised that 22q11.2 deletion syndrome is an excellent model for probing mechanisms underlying psychiatric disease, cardiovascular development and much more.

Background: The NHS Jewish BRCA Testing Programme is offering germline BRCA1 and BRCA2 genetic testing to people with ≥1 Jewish grandparent. Who have an increased likelihood of having an Ashkenazi Jewish (AJ) founder germline pathogenic variant (gPV) compared with the general population.Testing is offered via a self-referral, home-based saliva sampling pathway, supported by a genetic counsellor telephone helpline. A first-of-its-kind in the United Kingdom (UK) for population genetic testing, outside of research.

Methods: We reviewed data from germline testing of 5389 people who registered during the soft-launch phase (January 2023-January 2024) and their families to observe trends in uptake and outcomes of testing.

Results: Of the 5389 self-referrals, 4339 (80.5%) consented to testing. Of those with results returned, 2.3% (98/4,274) had a gPV (89.8% AJ founder and 10.2% non-AJ founder).Notably, the detection rate was higher in men (42/790, 5.3%) compared with women (56/3484, 1.6%), with the proportion reporting known BRCA variants within the family prior to consent also significantly increased (13.1% compared with 9.2%, respectively).

Conclusion: Overall detection rates of gPVs are similar to those reported elsewhere from Jewish population testing. The pathway, particularly for males, may attract uptake of testing by those previously aware of familial gPVs.

AKT1-related Proteus syndrome is an ultra-rare mosaic overgrowth disorder with tumour predisposition. We conducted a systematic review to determine the range and characteristics of these tumours. A systematic review was conducted to identify clinical reports and clinical series of Proteus syndrome published between 1983 and 2023. Affected individuals were selected based on existing Proteus syndrome diagnostic criteria and expert review. Six databases were searched, and each unique record was screened independently by two authors. Two authors extracted the following data from each included report per individual: demographics, tumour diagnosis, characteristics, outcome, clinical features of Proteus syndrome and report of AKT1 genetic testing. The literature searches yielded 3074 records of which 1239 were unique and screened. After screening, 190 records were included. These represented 205 unique individuals with Proteus syndrome. There were 38 individuals (19%) with at least one tumour diagnosis. The average age of tumour diagnosis was 15.1 years (SD 12.1). The most frequent tumour sites were genitourinary/gynaecologic (25 tumours, 53%) followed by the central nervous system (11 tumours, 23%). Most tumours were benign and treated with surgery alone. This systematic review provides a summary of Proteus syndrome-associated tumours from the literature. These data assist clinicians in the diagnosis and prognosis of these tumours. The study highlights the knowledge gap of possible adult-onset tumours and long-term outcomes, which requires further research. PROSPERO registration number CRD42021237914.

Background: This study explores the ethical and moral challenges faced by paediatric oncologists when they are informed of patient genomic results, particularly during molecular tumour boards (MTBs), highlighting the interplay between their clinic, research and expert roles.

Methods: This was an explanatory sequential mixed-methods study using a survey distributed to paediatric oncologists in Quebec followed by optional semi-structured interviews. Oncologists' attitudes and comfort levels with six hypothetical germline DNA results identified in a patient from a clinical vignette were assessed using Likert scales. Hypothetical genetic results represented ethical challenges of extended paediatric genomic sequencing. Interviews were conducted with a subgroup of participants to gain insight and context on key survey results.

Results: Eighty per cent (n=28) of oncologists in Quebec completed the survey; five participated in the interviews. Comfort levels of oncologists were influenced by the type of genetic result (expected, secondary, incidental finding), whether or not the oncologist was the patient's treating physician, and whether the information disclosed to the patient aligned with the information that they had received. Awareness of a genetic result was sufficient to trigger a feeling of responsibility and liability for that result.

Conclusion: Oncologists who take part in genomic sequencing initiatives and who attend MTBs have privileged access to genomic results, above what may be accessible to patients. This imbalance in knowledge contributes to moral discomfort experienced by oncologists who feel responsible for genomic information they are aware of. We propose recommendations applicable to consent processes, policies and pipelines for sharing genomic results.