Clinical Genetics最新文献

Lynch syndrome (LS) is an autosomal dominant hereditary disorder that increases the risk of various cancers, especially colorectal (CRC) and endometrial cancer (EC). It results from pathogenic variants in mismatch repair (MMR) genes-primarily MLH1, MSH2, MSH6, and PMS2. Population-specific variant frequencies emphasize the need for localized genetic studies. Methods This study investigated LS prevalence in Ceará, Northeast Brazil, analyzing 150 patients: 130 with CRC, 13 with endometrial cancer, and 7 with other tumors but a family history of LS-associated cancers. Researchers used next-generation sequencing (NGS) to examine 131 genes linked to hereditary cancer syndromes. Variants were classified as Lynch-syndrome associated (MMR genes) or non-Lynch-associated (non-MMR genes). Detection rates varied from 1.18 to 5.07 per 100,000 people; pathogenic variant prevalence ranged from 0 to 1.96 per 100,000 across microregions. Overall, the prevalence of MMR variants was 0.56 per 100,000, and 0.34 for non-MMR variants. MSH2 showed the highest number of pathogenic or likely pathogenic variants, followed by MSH6, PMS2, and MLH1. The study found a particular geographic distribution of LS-related variants. One novel MSH6 variant and two unreported non-Lynch variants (APC and SMAD4) were identified. Conclusions These findings highlight three novel variants in MSH6, APC, and SMAD4, and indicate that Ceará has a higher diversity and a unique spectrum of variants. This reinforces the importance of regional genetic screening and suggests the need to expand testing access, especially in high-risk areas, to improve the early detection and prevention of hereditary cancers in Northeast Brazil.

Dominant mutations in the calcium permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically result in skeletal dysplasia or peripheral neuromuscular disease. However, the full spectrum of TRPV4-related phenotypes remains incompletely defined. This study systematically reviewed the clinical and genetic features of 10 Chinese patients harboring various TRPV4 variants. In the cohort, six patients were diagnosed with spondylometaphyseal dysplasia Kozlowski type (SMDK) and four patients with metatropic dysplasia (MD). The most common features involved spinal deformity (platyspondyly, kyphosis or scoliosis), and lower-limb malalignments (genu varum, genu valgum, or leg-length discrepancy). Two patients with MD had neurological deficits. The R594H and P799R substitutions were the most recurrent variants in our study. A novel variant (c.1628T>G, p.L543R) in the S2-S3 loop was identified. The study seeks to improve diagnostic precision by combining genetic and radiographic assessment, and highlights the importance of early spinal surveillance and multidisciplinary care to prevent neurological complications underlying TRPV4-mediated disorders.

Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder marked by bone fragility and deformities. This study aimed to define the clinical and molecular characteristics of 21 OI patients from 15 unrelated Egyptian families. Most probands were analyzed by exome sequencing. In three consanguineous cases, variants were identified through SNP array-based homozygosity mapping followed by direct sequencing of a candidate gene. Genotype-phenotype correlations were additionally explored. Parental consanguinity was documented in 66.7% (10/15) of the total cohort and in 100% (8/8) of the families with autosomal recessive OI. Pathogenic or likely pathogenic variants were identified in 14 families, five of which were novel. A variant of uncertain significance was identified in the remaining family. COL1A1 and COL1A2 (n = 7) were the most commonly mutated genes, followed by CRTAP (n = 4), while variants in P3H1, WNT1, CREB3L1, and SEC24D were each identified in a single patient. The present study highlights the molecular heterogeneity of OI. In total, 15 distinct variants in seven OI-related genes were identified. We also report a particularly high number of OI lethal forms affecting 10 patients out of 21. The study adds further evidence for the utility of ES in the genetic diagnosis of OI, which facilitates counseling and personalized care.

This case highlights the complexity of diagnosing dual rare metabolic diseases and the importance of genetic testing in uncovering novel pathogenic variants. It has also contributed to expanding the clinical manifestation spectrum of B4GALT1-CDG, which is an ultra-rare disorder.

Müllerian anomalies are a collection of heterogeneous anatomical disorders of the female genital tract that present with complex clinical features of which severe subtypes like congenital aplasia of the vagina and uterus, may present with primary amenorrhea and dyspareunia, while mild cases like septate uterus, are often asymptomatic. Regardless of the types, the Müllerian anomalies impose both psychological and physical burdens on patients. Currently, the etiology of Müllerian anomalies remains largely unclear, which hinders early diagnosis and intervention. Although the advent of next-generation sequencing technologies has promoted a more comprehensive depiction of genetic features of Müllerian anomalies, there is still a lack of experimental validation for the functions of these genes, where some novel preclinical models having been applied in cancer fields may provide potentially available strategies. Thus, in this review, we aim to summarize the genetic defects and novel validation techniques associated with Müllerian anomalies. Elucidating the genetic mechanisms involving Müllerian anomalies can pave the way for the development of early diagnostic strategies and preventional measures in the future.

A novel biallelic missense mutation (c.470A>T) in the STN1 gene is responsible for Coats Plus Syndrome.

The genetic etiology of non-obstructive azoospermia (NOA) characterized by maturation arrest (MA) remains incompletely understood. A homozygous nonsense variant (c.119G>A, p.W40X) in KCTD19 was identified in two unrelated probands with NOA. This variant disrupts the evolutionarily conserved BTB domain and leads to the absence of the KCTD19 protein. Histological analysis revealed a complete absence of post-meiotic germ cells in the probands' testes, with spermatogenesis progressed into late prophase I (at least to the zygotene stage) but failed to complete meiotic division. Our findings demonstrate that bi-allelic loss-of-function variants in the meiotic gene KCTD19 cause complete MA. This study highlights an indispensable role of KCTD19 in meiotic prophase I, and expands the genetic spectrum underlying male infertility.

Stickler syndrome (SS) is clinically and genetically heterogeneous. Autosomal recessive Stickler syndrome (ARSS) is characterized by sensorineural hearing loss, myopia, retinal degeneration, vitreous anomalies, and epiphyseal dysplasia. It may also include midfacial hypoplasia, cleft palate, and skeletal manifestations. Currently, only 40 ARSS cases have been described, and just 4 are linked to pathogenic variants in the LOXL3 gene. A 20-year-old woman was referred to Medical Genetics due to Pierre Robin sequence, myopia, hearing loss, and distinct features. She was evaluated in early childhood with her sisters but was discharged without a specific genetic diagnosis. Polyhydramnios was detected in prenatal ultrasounds. Delivery occurred at 35 weeks. At birth, Pierre Robin sequence was evident, and she was admitted due to apnea. Complementary tests included karyotype, FISH 22q11, and screening for associated anomalies (cardiology, ophthalmology, ABR, and abdominal and cranial ultrasounds), all of which were normal. She had delayed speech development. She presents high myopia and bilateral conductive hearing loss, as well as nonspecific joint pain. She has two sisters with overlapping phenotypes. Both had cleft palate repair (one also with Pierre Robin sequence) and high-degree myopia. The first had a ventricular septal defect that spontaneously closed at age 5, and the second has conductive hearing loss. The physical examination highlights: microcephaly (head circumference < p1, -2.5 SD), downward-slanting palpebral fissures, midfacial and nasal ala hypoplasia, flat nasal bridge, elongated and flat philtrum, high-arched palate, absent uvula, joint hypermobility, shortening of third-fifth metacarpals and metatarsals, wide feet, and bilateral hallux valgus. Targeted sequencing of SS-associated genes revealed a likely pathogenic variant c.1735C>T and a variant of uncertain significance c.956G>A in the LOXL3 gene. Affected sisters carry both variants; both parents are healthy carriers. We report three new cases of SS due to previously undescribed biallelic variants in the LOXL3 gene. The clinical features are similar to those observed in other SS patients; however, digital anomalies and microcephaly have not been previously reported in patients with LOXL3 variants, thus expanding the phenotypic spectrum. This case highlights the importance of re-evaluating patients in light of ongoing advances in genetic diagnostics.

We report a novel SCN5A missense variant (c.655C>T (p.Arg219Cys)) in a family with non-dilated left ventricular cardiomyopathy, broadening the spectrum of SCN5A-related structural cardiac diseases. The proband, a 35-year-old man, presented with embolic stroke and myocardial fibrosis in the absence of ventricular dilation. He exhibited a significant arrhythmic burden, including premature ventricular complexes and a non-sustained ventricular tachycardia, prompting prophylactic subcutaneous defibrillator implantation. Genetic testing identified a heterozygous SCN5A variant, also present in five relatives with myocardial fibrosis of variable extent on cardiac magnetic resonance imaging. The variant affects a highly conserved residue within the voltage-sensing domain of the Nav1.5 channel and, according to ACMG criteria, is best classified as a variant of uncertain significance. Nevertheless, its segregation with disease and the established functional importance of this region of Nav1.5 suggest a possible role in the observed phenotype. This report highlights a structural cardiomyopathy phenotype potentially linked to SCN5A dysfunction and supports the growing recognition of overlap between ion channelopathies and cardiomyopathies.

DNA methylation (DNAm) signatures have emerged as valuable diagnostic biomarkers for rare genetic disorders. To date, the most widely used approach for establishing and validating these signatures has relied on array-based technologies. However, in clinical diagnostics, there is a growing shift from short-read sequencing (SRS) toward long-read sequencing (LRS) technologies. Recent advances in platforms such as Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT) enable direct assessment of DNAm from native DNA, offering improved resolution and reduced technical bias compared to array-based technologies. In this study, we compared DNAm profiles generated by LRS with those obtained from DNAm arrays. DNAm profiles of two individuals with pathogenic KMT2D variants were analyzed using DNAm arrays, LRS using PacBio and ONT, and ONT multiplexed sequencing with adaptive sampling. A support vector machine (SVM) classifier trained on array data, as well as the public classification platform EpigenCentral, yielded correct predictions for all LRS samples, underscoring the potential of LRS platforms in DNAm-based diagnostics. Our results suggest that DNAm profiles generated by LRS align well with DNAm signatures established using DNAm arrays, supporting their feasibility in clinical and research applications with the added benefit of simultaneous methylation and sequence analysis.