Application of Clinical Genetics最新文献

Aim: Turner syndrome (TS) is one of the most common genetic diseases in females, with typical physical features and comorbidities. Karyotype-phenotype associations and clinical significance of childhood versus adolescent/adulthood diagnosis are conflicting.

Purpose: Determining the role of certain TS karyotypes and early (<12 years of age) vs late (≥12 years) diagnosis in TS-specific phenotype and comorbidity penetrance.

Patients and methods: Retrospective analysis of baseline characteristics and 45 TS-specific features and comorbidities of 75 TS patients were diagnosed between 2009 and 2019 and followed-up until 2023 in our tertiary care center.

Results: Thirteen different karyotypes were detected: 45,X,inv(10), 45,X,inv(9)(15), 45,X, 46,X,i(Xq), 46,X,del(Xp), 46,XX,del(X)q21, 45,X/46,X,del(X), 45,X/46,X,+mar, 45,X/46,X,rX, 45,X/46,XX, 45,X/46,XY, 45,X/47,XXX, 46,X,i(Xq)/47,XX,i(Xq). The classic karyotype with 45X monosomy showed an increased risk for hypertrichosis (28.6% vs 7.5%, OR 4.93, 95% CI [1.23-19.73]), pterygium colli (34% vs 12%, OR 3.65, 95% CI [1.13-11.75]) and short stature (91% vs 75%, OR 3.56 [0.89-14.17]. Mosaic karyotypes had a smaller risk of pterygium colli (OR 0.28 [0.073-1.092]) and short stature (OR 0.29 [0.086-1.026]. 45X/46XX mosaicism was associated with an increased risk of hypertension (33% vs 6%, OR 7.75 [1.39-43.08]), and the presence of the iso (Xq) chromosome increased the risk of celiac disease (28% vs 3%, OR 13.2 [1.52-114.52]). 44/75 (58.6%) of the cohort were diagnosed at <12 years of age. In the <12-year-old diagnosis group, facial dysmorphism and low hairline, (OR 3.30, [1.26-8.65]), low-set ears (OR 2.51 [0.98-6.46]), and breasts abnormalities (OR 4.71 [1.72-12.83]), short stature (OR 4.09 [1.13-14.82]) and GH therapy (OR 4.93 [1.31-16.01]) occurred more frequently. If diagnosed <12 years, patients had a decreased risk of hepatosplenomegaly (OR 0.10 [0.02-0.50]) and hypertension (OR 0.097 [0.01-0.85]).

Conclusion: TS patients should be handled as a heterogenous group, as they seem to differ in the penetrance of phenotypical features of the disease and the risk of comorbidities depending on karyotype and age at diagnosis.

Alpha 1 Antitrypsin Deficiency (AATD) is a genetic condition that results from mutations in the SERPINA1 gene, which can lead to deficient or dysfunctional Alpha 1 Antitrypsin (AAT) protein production. AATD is linked to chronic obstructive pulmonary disease (COPD) and emphysema. In addition to pulmonary manifestations, AATD has also been associated with vascular pathology due to excessive protease activity, tissue degradation, and vessel stiffening. Early AATD diagnosis is crucial to prevent progressive lung damage and associated pathologies. Here, we present case reports of two patients with AATD from the Temple University Hospital Outpatient Clinic, who exhibited aneurysms of the aorta and splenic artery. AATD should be considered a genetic risk factor for aneurysms and vascular diseases, necessitating cardiovascular monitoring in affected individuals. This report emphasizes both the need for heightened awareness of AATD as a potential etiology of unexplained vascular aneurysms, as well as the need for screening for vascular pathology in patients with AATD-associated COPD and emphysema to facilitate early intervention and improve patient outcomes.

Background: Trimethylaminuria (TMAU) is a rare recessive genetic disorder with limited global prevalence. To date, there have been no official reports of TMAU cases documented in Saudi Arabia.

Purpose: In this study, we developed a liquid chromatography-mass spectrometry (LC-MS) method for the analysis of trimethylamine (TMA) and Trimethylamine N-Oxide (TMAO) in urine and plasma samples for the first reported case of TMAU in Saudi Arabia.

Patients and methods: A 41-year-old Saudi man was diagnosed with TMAU in National Guard Hospital. Blood and urine samples were collected to confirm the diagnosis of TMAU. In this study, we have studied LC-MS, cell culture, flow cytometry, adhesion assay and Sanger sequencing analysis. Additionally, in this study, we have selected 5 healthy controls.

Results: The results have revealed elevated TMA levels were present in both urine and plasma samples, while TMAO levels were significantly lower compared to control group. Further, we utilized plasma sample from the TMAU patient as novel model to investigate the potential effect of low TMAO on monocyte and endothelial cell function in vitro. DNA sequencing analysis identified a c.622G >T (p.Glu208*) which creates a premature stop codon in FMO3 gene.

Conclusion: Our findings revealed differential responses in monocytes and endothelial cells stimulated with plasma from the TMAU patient compared to plasma from non-TMAU patients. These distinct responses may be key modulators of endothelial function and contributes to vascular damage.

Androgen insensitivity syndrome (AIS) is an X-linked genetic disorder caused by mutations in the androgen receptor gene (AR), leading to impaired androgen signaling and resulting in varying degrees of undermasculinization in individuals with a 46,XY karyotype. This study aimed to expand the molecular landscape of AIS by identifying and characterizing pathogenic variants in the AR gene via next-generation sequencing (NGS). Molecular diagnostics revealed eight distinct variants within the AR gene, two of which had not been previously described. These include the following novel variants: c.3G>A, and c.1344_1345insTA. This study broadens the spectrum of known AR gene mutations associated with AIS and highlights the critical role of molecular diagnostics in the accurate classification of variants. These findings will aid in enhancing the clinical management and genetic counseling of individuals affected by AIS.

Wilms' tumor (WT) is the most common renal neoplasm in children. Despite its rapid growth, it is often asymptomatic. It most commonly occurs between the ages of 3 and 5, more frequently in girls. Numerous studies report an association between the occurrence of Wilms' tumor and genetic background. Treatment of bilateral Wilms' tumor (BWT) presents several challenges. Recent studies raise the issue of the influence of genetics on the development of BWT. We believe that our case report is innovative as it provides information on a rare clinical presentation and comprehensively addresses the potential impact of genetic studies on favorable treatment outcomes, which are discussed only in limited detail in the literature. The case description concerns a 2-year-old and a 5-month-old patient who presented with his mother due to a change in abdominal contour. In the medical history, the boy's mother had been treated for WT. Imaging of the abdominal cavity revealed the presence of pathological tissue changes in both kidneys. Based on this, stage V Wilms' tumor was diagnosed. The boy underwent a right-sided tumor nephrectomy followed by a left-sided heminephrectomy. He also received pre- and post-operative chemotherapy. Genetic testing revealed a deletion fragment of exon 8 and exons 9-10 on one allele of the WT1 gene. Despite optimistic data regarding overall survival in children with WT, a significant clinical issue remains with patients experiencing disease recurrence and bilateral BWT. Radical treatment is often required for such patients, which carries long-term consequences. Identifying patients at risk for familial WT or BWT allows for relatively early intervention and effective prevention. Furthermore, certain gene variants associated with WT can be considered prognostic biomarkers.

The aim of this study is to analyze available research on targeting signaling pathways for the development of new drugs in patients with T-cell acute lymphoblastic leukemia (T-ALL). This analysis focuses specifically on the role of LCK tyrosine kinase and mTOR signaling pathways in pediatric patients. Outcome: Current literature suggests that these pathways play a significant role in the regulation of T-cell cycles, making them potential therapeutic targets. However, despite promising findings, there remains a need for further research, particularly in pediatric populations, to fully understand the therapeutic implications and to optimize drug development. The conclusion drawn from this analysis highlights the significant influence of LCK and mTOR on T-cell cycle regulation, underscoring the importance of continued investigation in this area.

Introduction: Syndromic hearing loss (SHL) is characterized by distinctive clinical phenotypes as well as genetic and phenotypic heterogeneity. More than 400 species of SHL have been described, the majority of which are autosomal dominant.

Methods: 11 forms of SHL were obtained from 14 unrelated families with probands ranging in age from 5 to 78 months. The results of whole exome sequencing(WES), audiological characteristics, middle and inner ear radiological findings, and additional clinical phenotype characteristics were retrospectively analyzed.

Results: Fourteen people with SHL were found. Two of them had Waardenburg syndrome, two had Branchio-Oto-Renal syndrome, two had CHARGE syndrome, and one had Treacher Collins syndrome, Kleefstra syndrome, Muenke syndrome, Osteopathia Striata with Cranial Sclerosis, Ayme-Gripp syndrome, Tatton-Brown-Rahman syndrome, Stickler syndrome, or Stapes Ankylosis with Broad Thumbs and Toes. In this investigation, ten variants were first reported.

Discussion: The combination of a neonatal hearing screening and WES can diagnose syndrome-type hearing loss in infancy and childhood, according to our findings, expansion of the gene variant spectrum and phenotype for various age groups of SHL is essential and can provide valuable guidelines for clinical intervention decisions. It is imperative for medical practitioners to conduct diligent and prolonged patient monitoring due to the inherent variability in both the auditory impairment and the comprehensive clinical manifestation of SHL.

Background: Consanguinity, or the practice of marrying close relatives, is a common cultural tradition in Saudi Arabia, with rates among the highest in the world. This practice has significant implications for the prevalence and distribution of major single genetic defects and chromosomal abnormalities within the Saudi population.

Methods: Herein, using the BESTCare electronic medical record system (designed to streamline hospital operations, enhance patient care, and improve the overall efficiency of healthcare services; bestcare.ezcaretech.com) in a single tertiary centre, King Abdullah Specialized Children Hospital (KASCH) in Riyadh, Saudi Arabia, we performed a cross-sectional study for all patients referred to the hospital from the 1st January 2020 until 1st January 2022.

Results: The present study, which included 1100 individuals, found a high prevalence of consanguinity (64%) and a significant proportion of third-degree relatives (69%). The mean age of participants was 12.24 years, and the diagnostic rate using advanced molecular genetics techniques was 45%, with whole exome sequencing (WES) being the most common method (43%). The study also noted a significant delay in diagnosis for more than a year in 16% of cases, with a common neurodevelopmental phenotype (18%).

Conclusion: In conclusion, we revealed the prevalence of consanguineous marriages in the KASCH hospital in Riyadh, Saudi Arabia. We also highlighted the most frequently referred phenotype. These findings are consistent with previous research on the prevalence and impact of consanguinity on rare genetic disorders.

Introduction: Prolactin is a hormone secreted by the anterior pituitary gland essential for lactation. Non-physiological hyperprolactinemia characterized by serum prolactin levels exceeding 20 ng/mL in men and 25 ng/mL in women, often results from medication use or pituitary gland tumors. In a minority of cases, the cause of hyperprolactinemia remains unknown despite clinical investigations. Familial idiopathic hyperprolactinemia may stem from mutations in genes encoding prolactin (PRL) and its receptor (PRLR).

Methods: This study investigated genetic polymorphisms in PRL and PRLR genes using polymerase chain reaction (PCR) and Sanger sequencing in three sisters affected by familial idiopathic hyperprolactinemia. No mutations were found in these genes, prompting whole exome sequencing (WES) of the proband to identify other potentially involved genes.

Results: WES revealed a heterozygous missense substitution c.1301C>T (p.Ser434Phe) in the androgen receptor (AR) gene. Next-generation sequencing (NGS) for the AR gene confirmed that the proband and her two affected sisters, along with three asymptomatic sisters, were all heterozygous carriers of the mutation. Their father was hemizygous, while their mother had a normal genotype.

Conclusion: The heterozygous missense mutation in the AR gene found in this family with familial idiopathic hyperprolactinemia is not yet explained. Hence, further research is warranted to elucidate the functional implications of this mutation on AR and its role in the pathogenesis of hyperprolactinemia.