Explore the vast range of titles available.

Evidence suggests that protection against cancer confers a risk of type 2 diabetes and vice versa. This study shows that persons susceptible to cancer owing to a constitutive mutation in the tumor-suppressor gene PTEN also have heightened sensitivity to insulin and are obese. Epidemiologic evidence for a link among type 2 diabetes, obesity, and cancer has increased interest in the idea that some antidiabetes therapies may increase the risk of susceptibility to cancer, whereas others appear to offer protection. 1 Such a link is also supported by the discovery of several susceptibility loci for type 2 diabetes and their unexpected proximity to genes implicated in cell-cycle regulation. 2 The discovery of common genetic variants that influence both the risk of cancer and the risk of type 2 diabetes, in opposite directions, suggests that the two conditions may result from defects in the same pathway. 3 – . . .

Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies. Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.

PTEN hamartoma tumour syndrome (PHTS) comprises a group of genetic disorders with varied clinical presentations, including macrocephaly, developmental delay, and increased cancer susceptibility. Recent reports have highlighted the occurrence of tonsil-related issues in PHTS. Clinical data focusing on tonsil-related pathology and tonsillectomy details (indications, histology and post-operative complications) were collected from 53 patients with PHTS. Tonsil issues affected 58 per cent of the cohort, with 43 per cent requiring tonsillectomy. Primary indications for tonsillectomy included obstructive sleep apnoea (43 per cent), recurrent tonsillitis (17 per cent) and other causes (17 per cent). Tonsil-related problems were observed both before (45 per cent) and after (55 per cent) PHTS. Tonsillectomy with adenoidectomy was the predominant surgical intervention performed (87 per cent), spanning a broad age range (1-27 years old). Our findings highlight the complex nature of PHTS and its association with tonsil-related pathology, demonstrating its relevance for ENT surgeons. Early recognition and intervention are pivotal for managing sleep apnoea and the associated health problems.

Background Dominant polycystic kidney disease is common and usually presents clinically in adulthood. Recessive polycystic kidney disease is much less common and frequently presents antenatally or in the neonatal period with severe renal involvement. These are usually thought of as clinically distinct entities but diagnostic confusion is not infrequent. Case-diagnosis/treatment We describe an infant with antenatally diagnosed massive renal enlargement and oligohydramnios with no resolvable cysts on ultrasound scanning. He underwent bilateral nephrectomy because of respiratory compromise and poor renal function but died subsequently of overwhelming sepsis. Genetic analysis revealed that he had bilineal inheritance of abnormalities of PKD1 and no demonstrable abnormalities of PKD2 or PKHD1 . Conclusions Biallelic inheritance of abnormalities of PKD1 may cause extremely severe disease resembling autosomal dominant polycystic kidney disease (ADPKD) which can result in diagnostic confusion. Accurate diagnosis is essential for genetic counseling.

ObjectivesPTEN Hamartoma Tumour Syndrome (PHTS) is a heterogeneous autosomal dominant condition associated with pathogenic variants in the PTEN (Phosphatase and tensin homolog deleted on chromosome 10) gene.1 2 PHTS encompasses a group of genetic disorders with varied clinical presentations, including macrocephaly, autism spectrum disorder, developmental delay, epilepsy, hypermobility, mucocutaneous lesions, Lhermitte-Duclos and increased cancer susceptibility.2–4 Recent case reports have illustrated the occurrence of tonsil-related issues in PHTS,5 6 although there have been no cohort studies exploring tonsillar pathology in this distinct patient population. Our cohort study addresses this gap by reviewing the relationship between PHTS and tonsil pathology, particularly the prevalence, characteristics, and implications.MethodsA cohort of 53 patients with PTEN mutations known to the Wessex Clinical Genetics Service were included in the study. Clinical information was extracted from local electronic patient records from April to June 2023. Age, gender distribution, genetic mutations, indications for tonsillectomy, type of surgical procedure, histology and post-operative complications were analysed.ResultsTonsils issues were prevalent in 58% of the cohort, with 74% undergoing subsequent tonsillectomy. This accounted to 43% of the total cohort, significantly greater than the 13.6% of the general population undergoing tonsillectomy.7 Obstructive sleep apnoea (43%) was the most common primary indication for tonsillectomy, followed by recurrent tonsillitis (17%), and other causes (17%). There was a similar proportion of tonsil-related problems observed before (45%) and after (55%) PHTS diagnosis. The mean age of PHTS patients undergoing tonsillectomy was 7.8 years, with a broad age range (1 to 27 years). The predominant (87%) surgical intervention performed was tonsillectomy with adenoidectomy and 26% experienced issues post-operatively.ConclusionThis study highlights the association of PHTS with tonsillar pathology throughout early life. Macrocephaly, developmental delay with or without autism and extreme tonsillar hypertrophy are indicators of an underlying PHTS diagnosis in children. Vigilant clinical evaluation by paediatricians and multidisciplinary collaboration, including the early recognition of tonsil-related manifestations and intervention are pivotal for managing PHTS patients and their associated health problems.ReferencesLiaw D, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997Marsh DJ, et al. PTEN mutation spectrum and genotype-phenotype correlations in bannayan-riley-ruvalcaba syndrome suggest a single entity with cowden syndrome. Hum Mol Genet. 1999.Celebi JT, et al. Germline PTEN mutations in three families with Cowden syndrome. Exp Dermatol. 2000.Lachlan KL, et al. Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet. 2007.Piccione M, et al. PTEN hamartoma tumor syndromes in childhood: Description of two cases and a proposal for follow-up protocol. Am J Med Genet A. 2013.Abdul LZ, et al. Bannayan Riley Ruvalcaba Syndrome. Annals Academy of Medicine. 2010.Šumilo D, et al. Incidence of indications for tonsillectomy and frequency of evidence-based surgery: a 12-year retrospective cohort study of primary care electronic records. Br J Gen Pract. 2019.

Duplications involving the X chromosome, in which the duplicated region is not subject to inactivation, are rare. We describe four distal Xq duplications, in three males and one female, in which the duplicated X chromosomal material is active in all cells. The infantile phenotype bears some resemblance to that of the Prader-Willi syndrome, presenting with initial feeding difficulties, hypotonia and, sometimes, with cryptorchidism. However, the severity of the phenotype is not simply related to the size of the duplication and so variations in gene expression, gene disruption or position effects from breakpoints should be considered as explanations. We have compared the clinical, cytogenetic and molecular findings of our patients with those previously reported. This has enabled us to question the suggestion that duplication of the gene SOX3 is the cause of hypopituitarism and that duplication of Filamin A is the cause of bilateral periventricular nodular heterotopia/mental retardation syndrome (BPNH/MR). We have also narrowed the putative critical interval for X-linked spina bifida.

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations. Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1 , 2 ). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%) 3 , suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance 4 , 5 . De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations 6 , 7 . We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings 8 . Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4 , CDK13 and PRKD1 . Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Background: The most commonly reported phenotypes described in patients with PTEN mutations are Bannayan–Riley–Ruvalcaba syndrome (BRRS), with childhood onset, macrocephaly, lipomas and developmental delay, and Cowden Syndrome (CS), an adult-onset condition recognised by mucocutaneous signs, with a risk of cancers, in particular those of the thyroid and breast. It has been suggested that BRRS and CS are the same condition, but the literature continues to separate them and seek a genotype–phenotype correlation. Objective: To study the clinical features of patients with known PTEN mutations and observe any genotype–phenotype correlation. Methods: In total, 42 people (25 probands and 17 non-probands) from 26 families of all ages with PTEN mutations were recruited through the UK clinical genetics services. A full clinical history and examination were undertaken. Results: We were unable to demonstrate a genotype–phenotype correlation. Furthermore, our findings in a 31-year-old woman with CS and an exon 1 deletion refutes previous reports that whole exon deletions are only found in patients with a BRRS phenotype. Conclusion: Careful phenotyping gives further support for the suggestion that BRRS and CS are actually one condition, presenting variably at different ages, as in other tumour-suppressor disorders such as neurofibromatosis type 1. This has important counselling implications, such as advice about cancer surveillance, for children diagnosed with BRRS.

Purpose Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3–3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue. Design Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters). Results Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation. Conclusions Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.

GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE–trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay. Phenome-wide analysis in the UK Biobank identifies GC-rich tandem repeat expansions associated with a range of traits, including a GCC expansion in AFF3 contributing to intellectual disability.