Clinical Genetics最新文献

Multilocus genomic variations (MGVs), defined as pathogenic variants in two or more independent loci, are increasingly recognised in individuals with complex clinical phenotypes, particularly in highly consanguineous populations. Recent advancements in technologies, including exome and whole-genome sequencing, have revolutionised the diagnostic landscape, facilitating the identification of MGVs. This retrospective study analysed the genetic data of 80 patients referred to our centre in Türkiye, each with at least two molecularly confirmed genetic diagnoses. Tests included standard karyotyping, chromosomal microarrays, targeted panels, and exome sequencing, with pathogenicity classified according to American College of Medical Genetics (ACMG) criteria. The cohort included diverse phenotypes, with a significant proportion arising from consanguineous unions (48.7%). Copy number variations were identified in 16% of cases, and 21% harboured variants in genes associated with actionable secondary findings. Patients exhibited distinct (82.5%) or overlapping (17.5%) phenotypes, supported by semantic similarity scores and protein-protein interaction analyses. This largest Turkish cohort on MGVs highlights the impact of consanguinity on rare disease genetics and underscores the value of comprehensive genomic testing. Accurate interpretation is vital for effective counselling and patient care.

Duchenne/Becker muscular dystrophy (DMD/BMD) is a severe progressive form of muscular dystrophy which manifests in boys at the age of 1-8 years. The disorder is mainly characterized by proximal muscle weakness, which leads to impaired movement and subsequently total disability. DMD/BMD is caused by pathogenic variants in the DMD gene, which lead to a deficit in the production of various dystrophin isoforms. Seeing as the disorder was characterized many years ago, the DMD mutation spectrum has been described by multiple authors around the world. The most common variants are gross deletions and duplications of one or multiple exons, comprising 55%-65% and 6%-11% of all variants in this gene respectively. Other DMD/BMD cases (20%-30%) are caused by point variants. The current study describes the full spectrum of point variants in the DMD gene among Russian patients, analyzing the variant distribution in the gene and establishing the repeating variants in the examined cohort. Such comprehensive analysis is essential for genetic counseling and disorder prognosis, as well as determining the suitable therapeutic approach in each particular case.

Lissencephaly is a genetically heterogeneous condition caused by aberrant neuronal migration. Cerebellar hypoplasia has been commonly associated in some subtypes of lissencephaly, notably the tubulinopathies. CDK5 is a microtubule-associated protein, and its defective function has been implicated in various neurodevelopmental and neurodegenerative disorders. Biallelic loss-of-function variant in CDK5 has been reported to cause lissencephaly type 7 in a single family to date. We describe an infant with diffuse agyria, cerebellar hypoplasia, and agenesis of the corpus callosum harboring a homozygous novel missense variant c.149G>A in CDK5. She had refractory seizures, pyramidal signs, microcephaly, and growth failure. She did not achieve any developmental milestones and succumbed at 4 months of age. The disease course and severity were similar to those observed in the patients in the first report, who had a splicing defect leading to loss-of-function. In silico functional analysis showed that the variant c.149G>A (p.Arg50Gln) caused instability of the CDK5 protein structure, potentially causing functional disruption. Functional analysis of the p.Arg50Gln variant, using a yeast complementation assay, showed a deleterious impact of the variant. In conclusion, this is the second family with CDK5-related lissencephaly type 7.

Aarskog-Scott syndrome (AAS, MIM#305400) is an X-linked disorder characterized by recognizable facial features, short stature, and genitourinary and skeletal malformations. AAS is attributed to pathogenic variants in FGD1, and ~60 patients with a genetic diagnosis have been reported to date. We hereby present a molecularly confirmed cohort of 14 male AAS patients from 13 families. Among 14 patients, 12 were referred during childhood, while two were referred at adulthood due to infertility. Six out of 11 patients with available records had antenatal manifestations, comprising shortened tubular bones, growth restriction, polyhydramnios, pes equinovarus, increased nuchal translucency, fetal hypokinesia, echogenic intracardiac focus, and ambiguous genitalia. In addition to well-described AAS findings, distinctive features observed in multiple patients included variable skin findings (n = 5), renal malformations (n = 2), muscular build (n = 2), and infertility (n = 2). Cardiac (n = 4) and ocular manifestations (n = 6) were identified at significantly higher rates than previously reported. This cohort also presents new patients with osteochondritis dissecans and oligo/azoospermia, providing further evidence to acknowledge these once-reported findings as part of the disease spectrum. Eleven different FGD1 variants, including seven novel ones, were identified through targeted FGD1 sequencing. Two variants were found to be recurrent, detected in two independent families. Our study provides additional insights into the clinical and genotypic landscape of AAS through the largest molecularly confirmed cohort, including two adult patients.

The DOCK3 gene (NM_004947.5) is located on chromosome 3p21.2 spanning 53 exons and encodes the dedicator of cytokinesis 3 protein. DOCK3 belongs to the family of guanine nucleotide exchange factors (GEFs) that activate GTPases. DOCK3 is expressed almost exclusively in the central nervous system and has been shown to promote axonal outgrowth. Biallelic disruptions of DOCK3 are implicated in a neurodevelopmental disorder presenting with intellectual disability, hypotonia and ataxia (OMIM: 618292). We report a 9-year-old female with global developmental delay, moderate intellectual disability, wide-based and ataxic gait, hypotonia, benign nocturnal myoclonus, bifid uvula, moderate obstructive sleep apnea, and alternating esotropia. Prior to enrollment in the Undiagnosed Rare Disease Clinic (URDC), the patient's clinical exome testing was negative. The subsequent enrollment in URDC allowed further research investigations through whole genome sequencing (GS) that identified two compound heterozygous variants in the DOCK3 gene, ultimately yielding an unequivocal definitive molecular diagnosis.

The EMC10-Related Neurodevelopmental Disorder (also known as NEDDFAS for Neurodevelopmental Disorder with Dysmorphic Facies and variable Seizures) is an autosomal recessive syndrome characterized by global developmental delay, intellectual disability, microcephaly, seizures, renal abnormalities, and minor facial dysmorphic features. We report an individual with developmental delay and intellectual disability, harboring a homozygous pathogenic mutation in EMC10 (NM_206538.4, c.343C>T, p.(Arg115Ter)), identified through exome reanalysis. Notably, this patient presents gingival hyperplasia and scoliosis, features previously associated with EMC1 mutations, but not with EMC10 mutations. Here, we not only broaden the phenotypic spectrum of EMC10-Related Neurodevelopmental Disorder, but also underscore the importance of exome reanalysis in clinical practice.

Limited literature exists on cases diagnosed with trisomy 9 mosaicism. In addition to case studies and small "n" studies, the Tracking Rare Incidence Syndromes (TRIS) project has provided results for 39 cases from a parent registry. This article provides data for 67 additional cases from the TRIS project database. Results describe physical characteristics and an overview of presenting medical conditions, including cardiac anomalies along with feeding and respiratory difficulties in the immediate postnatal period. Data are largely aligned with previous findings. Future research is needed to confirm the findings. Implications are offered for collaboration for care and management with parents and caregivers.

This study aimed to comprehensively characterize the molecular spectrum of thalassemia by retrospectively analyzing genetic screening results from a large cohort of individuals. Peripheral blood samples were collected from 26 047 individuals seeking care at the Departments of Obstetrics and Gynecology, Pediatrics, Reproductive Medicine, and Hematology across multiple regional hospitals in Guizhou Province, China. Thalassemia gene mutations were analyzed using targeted third-generation sequencing (TGS) to assess the mutation spectrum in this population. Of the cohort, 5099 individuals were identified as thalassemia carriers, yielding an overall carrier rate of 19.58%. The carrier rates differed significantly between the southern and northern regions of Guizhou (p < 0.001). α-thalassemia included 40 distinct genotypes, β-thalassemia comprised 33 genotypes, and cases with concurrent α- and β-thalassemia mutations exhibited 47 unique genotypes. A total of 17 distinct mutations were identified in the α-thalassemia gene and 26 in the β-thalassemia gene. The mutation spectrum in Guizhou showed significant differences when compared to other southern Chinese populations, with notable regional variations within Guizhou itself. This study highlights the substantial genetic diversity and distinct mutation patterns of thalassemia in Guizhou Province. These findings provide valuable insights into the distribution of thalassemia genotypes and alleles, which can inform genetic counseling and prenatal screening strategies tailored to this population.

Early-onset Marfan syndrome (eoMFS) is a severe and rare form of Marfan syndrome characterized by severe atrioventricular valve insufficiency developing before or shortly after birth. It is unclear which factors (interventions and/or genotype) influence survival. Forty-one individuals with eoMFS with a fibrillin-1 gene (FBN1) variant in exon 24-32 (CRCh37) were included. At the last follow-up, 14/41 (34%) were alive (8 months-18 years) and 27/41 (66%) were deceased. Median age of death was 1 month and 88% of the deaths occurred before 5 months of age. More individuals alive past the age of 16 months versus those who were deceased before that age had undergone cardiovascular surgery at an older age (13 months, range 3-72, vs. 2 months, range 2-2, p = 0.03). Survival was better in those with single amino acid substitutions/small in-frame deletions than in those with large in-frame deletions (p = 0.007), but variants involving a cysteine substitution in an EGF-like domain versus those involving other amino acids did not significantly influence survival. EoMFS ranges from a (pre-)neonatal life-threatening disorder to a disorder with enhanced survival, creating a window for cardiovascular surgery. Individuals with single amino acid substitutions/small in-frame deletions had better survival compared to those with variants significantly impacting exon 24-32 length.

Small nucleolar ribonucleic acids (snoRNAs) have emerged as crucial regulators in various biological processes and have garnered significant attention for their potential roles in cancer. These noncoding ribonucleic acids (RNAs) primarily guide ribosomal RNA (rRNA) pseudouridylation and 2'-O-methylation modifications and exhibit stable expression in the serum, making them promising biomarkers and therapeutic targets. Digestive tract cancer poses a severe global health threat due to its high mortality rate and difficulty in early detection. Understanding the molecular mechanisms underlying tumor development is critical for improving diagnostic and therapeutic strategies. Small nucleolar RNAs, with their diverse functions and stable presence in biological fluids, offer a unique opportunity to address these challenges. Small nucleolar RNAs are a class of small noncoding RNAs mainly located in the nucleolus of eukaryotic cells. They play essential roles in the maturation and modification of rRNAs, transfer RNAs, and small nuclear RNAs. They also participate in alternative splicing regulation and exhibit microRNA-like functions, influencing various cellular processes. Abnormal expression of snoRNAs has been closely linked to the development, invasion, and metastasis of digestive system tumors. Given their stable expression in serum and the ability to function independently of host genes, snoRNAs hold great potential as biomarkers for early screening, prognosis prediction, and therapeutic targets in digestive system tumors. Their involvement in key signaling pathways and molecular mechanisms provides a foundation for developing targeted therapies and improving patient outcomes. This review highlights the significance of snoRNAs in digestive system tumors, their biological roles, connections to cancer progression, and potential clinical applications. Further exploration of snoRNAs is expected to provide new insights into the diagnosis and treatment of digestive system tumors.