Journal of Medical Genetics最新文献

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: PTEN hamartoma tumour syndrome (PHTS) encompasses distinct syndromes, including Cowden syndrome resulting from PTEN pathogenic variants. Missense variants account for 30% of PHTS cases, but their classification remains challenging. To address these difficulties, guidelines were published by the Clinical Genome Resource PTEN Variant Curation Expert Panel.

Methods: Between 2010 and 2020, the Bergonie Institute reference laboratory identified 76 different non-truncating PTEN variants in 166 patients, 17 of which have not previously been reported. Variants were initially classified following the current guidelines. Subsequently, a new classification method was developed based on four main criteria: functional exploration, phenotypic features and familial segregation, in silico modelling, and allelic frequency.

Results: This new method of classification is more discriminative and reclassifies 25 variants, including 8 variants of unknown significance.

Conclusion: This report proposes a revision of the current PTEN variant classification criteria which at present rely on functional tests evaluating only the phosphatase activity of PTEN and apply a particularly stringent clinical PHTS score.The classification of non-truncating variants of PTEN is facilitated by taking into consideration protein stability for variants with intact phosphatase activity, clinical and segregation criteria adapted to the phenotypic variability of PHTS and by specifying the allelic frequency of variants in the general population. This novel method of classification remains to be validated in a prospective cohort.

Background: The Upstream Binding Transcription Factor (UBTF) gene encodes two nucleolar proteins, UBTF1 and UBTF2. UBTF1 regulates rRNA transcription by RNA polymerase I, while UBTF2 regulates mRNA transcription by RNA polymerase II. A recurrent de novo dominant mutation c.628G>A (p.Glu210Lys) has been identified as a gain-of-function mutation associated with childhood onset neurodegeneration with brain atrophy (CONDBA). Evidence from large-scale population databases and Ubtf^+/- mouse models indicates that UBTF haploinsufficiency is not tolerated.

Methods: Three unrelated patients with global developmental delay and distinctive facial features were recruited for the study. Whole exome sequencing (WES) was performed to identify potential genetic abnormalities. Additionally, copy number variation analysis was conducted based on the WES data.

Results: All three patients exhibited intellectual disabilities, social challenges and developmental delays in language and gross motor skills. Distinctive facial features included a wide forehead, sparse eyebrows, hypertelorism, narrow palpebral fissures, single-fold eyelids, a flat nasal bridge, anteverted nares, a long philtrum and a thin upper lip. Additionally, patient C presented with more severe language delay, recurrent hepatic dysfunction and an atrial septal defect. Patient A was found to have a nonsense variant, c.1327C>T (p.R443Ter), in the exon 13 of UBTF. Patients B and C both carried a heterozygous deletion encompassing the UBTF gene.

Conclusion: In this study, we analysed the detailed phenotypes associated with UBTF haploinsufficiency, which, to our knowledge, have not been previously reported. We propose that UBTF haploinsufficiency-related global developmental delay and distinctive facial features, without neuroregression, constitute a new syndrome distinct from CONDBA.

Purpose and scope: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times.

Methods of statement development: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute.

Results and conclusions: We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.

In children, 15% of nephrotic syndromes are steroid-resistant (SRNS); approximately 30% of early onset SRNS have a genetic origin, with more than 100 causal genes described so far. SRNS can be syndromic, if associated with signs and symptoms affecting other organs or systems, such as the central nervous system, the heart or the eyes. Patients with SRNS are at high risk of chronic kidney disease and progressive renal failure, and as such need multidisciplinary care, centred on renal protection. Recently, K acetyltransferase 2B (KAT2B) loss of function was identified as a risk factor for morphological and functional defects in Drosophila nephrocytes; in vitro knockdown of KAT2B also impaired the adhesion and migration ability of human podocytes.Here we provide the first clinical description of a family affected by a loss of function mutation of KAT2B Clinically, both siblings presented with early onset SRNS and bilateral cataract, without neurological or heart defects. Renal function was maintained in the teenage years; nephrotic-range proteinuria was insensitive to immunosuppressive therapies. Therefore, mutations of KAT2B should be sought in patients with unexplained syndromic SRNS affecting the eye.

Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal disorder, primarily characterised in adults by cutaneous features, pulmonary cysts that predispose to spontaneous pneumothorax and renal tumours. The syndrome is caused by pathogenic variants in the FLCN tumour suppressor gene, which plays a role in the mammalian target of rapamycin (mTOR) signalling pathway. We present the case of a newborn infant diagnosed with BHDS, who died of sudden cardiac death due to complications from cardiac rhabdomyoma. This is only the second reported case of such an association. Both cases were initially misdiagnosed with tuberous sclerosis complex, highlighting the diagnostic challenges. We discuss this differential diagnosis and suggest that cardiac rhabdomyomas, although rare, may be associated with BHDS and potentially life threatening. Therefore, we recommend cardiac screening in newborns at risk.

Background: For female patients with Lynch syndrome (LS), endometrial cancer (EC) is often their first cancer diagnosis. A testing pathway of somatic tumour testing triage followed by germline mismatch repair (MMR) gene testing is an effective way of identifying the estimated 3% of EC caused by LS.

Methods: A retrospective national population-based observational study was conducted using comprehensive national data collections of functional, somatic and germline MMR tests available via the English National Cancer Registration Dataset. For all EC diagnosed in 2019, the proportion tested, median time to test, yield of abnormal results and factors influencing testing pathway initiation were examined.

Results: There was an immunohistochemistry (IHC) or microsatellite instability (MSI) test recorded for 17.8% (1408/7928) of patients diagnosed with EC in 2019. Proportions tested varied by Cancer Alliance and age. There was an MLH1 promoter hypermethylation test recorded for 43.1% (149/346) of patients with MLH1 protein IHC loss or MSI. Of patients with EC eligible from tumour-testing, 25% (26/104) had a germline MMR test recorded. Median time from cancer diagnosis to germline MMR test was 315 days (IQR 222-486).

Conclusion: This analysis highlights the regional variation in recorded testing, patient attrition, delays and missed opportunities to diagnose LS, providing an informative baseline for measuring the impact of the national guidance from the National Institute for Health and Care Excellence on universal reflex LS testing in EC, implemented in 2020.

Pathogenic variants of WD repeat domain 45 (WDR45) cause neurodegeneration with brain iron accumulation 5 (NBIA5), which is characterised by progressive neurological regression and brain iron accumulation in adulthood. Early diagnosis of NBIA5 patients is difficult because they often show only a non-specific developmental delay in childhood, but it is essential for lifelong medical management. We investigated 32 females with developmental delays for coding variants of WDR45 using Sanger sequencing. Whole-genome sequencing (WGS) and X chromosome inactivation (XCI) analysis were also performed. We identified two disease-causing variants, one of which was a novel stop-loss variant, c.1051delG p.(Val351CysfsTer60), in a female with severe developmental delay from early infancy with epileptic spasms. The XCI analysis (which we originally developed) suggested a random pattern in white blood cells. WGS did not reveal any other pathogenic variants, including those in two iron transporter genes. Together with our previous findings in the WGS study, WDR45 variants accounted for 12% (6/51) of the females with developmental delay, suggesting that WDR45 is a major gene in females with developmental delay. Pathogenic variants of WDR45 result in various phenotypes that do not necessarily correlate with variant types or XCI skewing patterns.

Background: Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant muscular disorder mainly caused by the contraction and hypomethylation of the D4Z4 repeat array in chromosome 4q35. Prenatal diagnosis of FSHD1 is challenging due to the highly repetitive and long genomic structure. In this study, a pregnant woman diagnosed with FSHD1 using optical genome mapping sought assistance for a healthy offspring.

Methods: At the 17th week of gestation, she underwent amniocentesis, and genomic DNA (gDNA) was extracted from amniocytes. Whole-genome sequencing of the gDNA was performed using the nanopore MinION platform.

Results: Despite a sequencing depth of only 7.3×, bioinformatic analyses revealed that the fetus inherited four D4Z4 repeat units with the permissive 4qA from the mother and the eight D4Z4 repeat units with the non-permissive 4qB from the father. To validate the results, SNP-based linkage analyses were conducted with gDNA from the proband, the proband's father and proband's amniocytes. Results indicated that the fetus inherited the maternal pathogenic haplotype based on 144 informative SNPs. Linkage analysis was consistent with the nanopore sequencing.

Conclusion: Nanopore sequencing proves to be an accurate and direct method for genetic testing of monogenic diseases at the single-nucleotide level. This study represents the first application of nanopore sequencing in the prenatal diagnosis of FSHD1, providing a significant advantage for patients with de novo mutations.