Clinical Genetics最新文献

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.

Pathogenic variants in ADAMTSL4 are an important cause of isolated ectopia lentis with an increasing number of genetically confirmed cases internationally. We sought to better describe ocular features seen with pathogenic variants in ADAMTSL4. We performed a retrospective, multicenter study examining the phenotypic and genotypic spectrum of ADAMTSL4-associated ocular disease. We identified 41 individuals from 32 families with genetically confirmed ADAMTSL4-related disease across six tertiary referral centers across Europe. Identified participants had a young age of diagnosis (median 1.3 years) and a highly myopic refractive error (mean SE -10.27 D). A diagnosis of ectopia lentis et pupillae was made in a third of cases, with a younger age at diagnosis (median 0.5 years). Subluxation tended to be in the inferior direction (~33%). Zonules were noted to be missing or absent in the majority of cases. Sixteen different pathogenic variants in ADAMTSL4 were reported. A previously reported 20-bp deletion (c.767_786del) was highly prevalent in this cohort (23/32), and all ectopia lentis et pupillae cases carried this variant. ADAMTSL4-related disease tends to present at a younger age and be associated with higher myopia than other forms of ectopia lentis (such as FBN1). Early identification of typical phenotypic features alongside genetic testing can aid early, precise diagnosis and prevent unnecessary investigations.

KDM3B encodes a histone lysine demethylase and is involved in transcriptional regulation. Patients with heterozygous pathogenic variants in KDM3B are diagnosed with Diets-Jongmans syndrome (DIJOS), a rare autosomal dominant disorder characterized by intellectual disability, developmental delay, distinctive facial features, and short stature. Here, we report the identification of a novel frameshift variant in KDM3B in a seven-month-old male patient evaluated for small stature, microcephaly, facial asymmetry, and mild gross motor delays. A trio exome with results at 14 months of age identified a de novo pathogenic variant in KDM3B, c.2446del p.(Ser816Valfs*6). At 15 months of age, the patient demonstrated additional clinical findings of mild bilateral epicanthal folds, short philtrum, mildly downslanting palpebral fissures, broad nasal bridge, and mildly simplified ears, while his physical and behavioral development remained age appropriate. This is the youngest known patient with a de novo KDM3B variant identified before 1 year of age. Unlike other DIJOS patients, the current proband does not have signs of significant neurodevelopmental delay. Additionally, he has unilateral facial asymmetry, which had not been previously reported in DIJOS patients. This patient's unique and evolving clinical features further our understanding of the phenotypic diversity and may inform the long-term prognosis of DIJOS.

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.

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.

Genome sequencing (GS) has emerged as the gold standard for diagnosing patients with rare diseases. As with many emerging technologies, equitable access remains a concern. To evaluate the feasibility and diagnostic impact of expanding access to GS, we report our experience implementing CincyKidsSeq, a prospective study offering GS as a "proband-first" test. Participants of all ages with at least one symptom were referred by genetics or non-genetics healthcare providers, or alternatively, were self-referred from February 2024 to February 2025. This diverse referral structure was evaluated for diagnostic yield while maintaining clinical oversight through a hybrid model in which reportable variants are delivered through genetic providers. The overall diagnostic yield of GS on 313 participants was 22% in the unstratified cohort. Self-referred patients had a higher diagnostic yield (11/33; 33%), compared with patients referred by a non-genetics provider (27/98; 27%), or genetics provider (32/182; 18%). Self-referred individuals were older, more likely to be female, frequently test-naïve, and utilized fewer human phenotype ontology (HPO) terms (p value = 0.0016). Self-referral may serve as an effective and complementary pathway for improving access to GS. Empowering families to initiate GS may be a reasonable pathway for an alternative model for genetic service delivery.

A recurrent de novo germline variant in the MAX gene, p.(Arg60Gln), has recently been associated with polydactyly-macrocephaly syndrome in six unrelated individuals. Affected individuals presented with progressive macrocephaly, post-axial polydactyly, developmental delay, autistic features and a series of craniofacial, brain, cardiac, ocular, and renal anomalies. Here, we describe two unrelated female probands with the known recurrent MAX variant, c.179G>A p.(Arg60Gln), who presented with the emerging phenotypes of the MAX-associated syndrome. We also propose that genitourinary abnormalities, including Mayer-Rokitanski-Kuster-Hauser syndrome in one individual, may constitute an expansion of the known phenotype. These findings contribute to the current knowledge regarding the phenotypic spectrum of MAX-associated polydactyly-macrocephaly syndrome.

A homozygous LZTR1 frameshift variant resulting from maternal uniparental disomy of chromosome 22 [UPD(22)] is associated with bone marrow failure and dysmorphic features distinct from those of Noonan syndrome. Biallelic LZTR1 variants lacking the second BTB domain may underlie a rare clinical phenotype characterized by bone marrow failure.

Huntington's disease (HD) has prevalent, life-altering consequences for affected individuals, relatives, familial caregivers and systemic functioning. However, the shared psychosocial impacts of HD across family systems are inadequately understood, and a synthesis of evidence regarding these experiences is currently lacking. This thematic synthesis provides an up-to-date integration of qualitative research describing psychological, social and relational difficulties experienced by HD families. A systematic search across PsycINFO, CINAHL, MEDLINE and Scopus identified nine qualitative studies. Four interconnected superordinate themes were developed, describing a disintegration of HD families from society, HD-related emotional and psychological burdens, an interplay of extrinsic stressors and recalibration of the family system. These findings extend existing knowledge about systemic impacts of HD, highlighting diverse and pervasive psychological and social difficulties faced by families. The synthesis recommends the development of interventions and clinical understandings to appropriately support family systems around psychosocial and relationship dynamic challenges in the unique context of HD.