Clinical Genetics最新文献

The subcortical maternal complex (SCMC) is crucial for the oocyte-to-embryo transition, and genetic variants in SCMC genes have been associated with early embryonic arrest (EEA). In this study, we performed whole-exome sequencing on 303 independent females with EEA and identified 16 patients with biallelic pathogenic variants in SCMC genes (NLRP2, NLRP5, PADI6, and TLE6), accounting for 5.3% of EEA cases. NLRP5 had the highest prevalence, with 7 out of 16 cases (43.8%). A total of 23 novel variants were identified, including 13 missense, eight loss-of-function, one in-frame insertion, and one large 6.9 kb deletion. Functional predictions using mCSM indicated that nine missense variants destabilize SCMC structure. Additionally, RT-PCR and cDNA sequencing demonstrated that the synonymous variant in TLE6 (c.180G>A) impacts splicing and induces nonsense-mediated decay. Taken together, our findings revealed that novel biallelic variants in SCMC genes were associated with human EEA, which expands the spectrum of genetic causes and facilitates the genetic diagnosis of female infertility with EEA.

STAR syndrome is a very rare X-linked dominant disorder characterized by the association of toe syndactyly, facial dysmorphism including telecanthus and a broad nasal tip, and anogenital and renal malformations. We hereby report a patient with a novel frameshift mutation in CCNQ, the STAR syndrome causative gene. More importantly, the patient presented hitherto unreported clinical features, namely toe polydactyly in addition to syndactyly, and a supernumerary nipple. This nineteenth reported case further broadens the phenotypic spectrum of STAR syndrome.

Inherited retinal diseases (IRDs) constitute a heterogeneous group of clinically and genetically diverse conditions, standing as a primary cause of visual impairment among individuals aged 15-45, with an estimated incidence of 1:2000. Our study aimed to comprehensively evaluate the genetic variants underlying IRDs in the Turkish population. This study included 50 unrelated Turkish IRD patients and their families. Genomic DNA was extracted from each participant, and candidate variants were identified via next-generation sequencing to determine their pathogenicity. We detected variants in 58% of the patients, of which six novel variants were identified. Among these, 16 cases exhibited variants associated with retinitis pigmentosa and Stargardt disease, while 13 presented variants linked to other retinal diseases. The spectrum of identified variants included 21 homozygous cases and five compound heterozygous variants, both indicative of autosomal recessive inheritance. Three cases revealed heterozygous variants suggestive of autosomal dominant inheritance, and two cases featured hemizygous variants suggestive of X-linked inheritance. Importantly, no matches with copy number variants were detected in our analysis. This study comprehensively portrays clinical and genetic profiles within the Turkish population affected by IRDs. Identifying novel variants and delineating inheritance patterns contribute to a deeper understanding of the genetic diagnosis of IRDs, paving the way for more precise diagnostic and therapeutic interventions.

Silver-Russell Syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction. Most cases are caused by an imprinting error either with hypomethylation of the Imprinted Control Region 1 at 11p15.5, or maternal uniparental disomy of chromosome 7. Approximately 40% of the cases have unknown etiology, thus distinct mechanisms have been described in association with the syndrome. Here, we present a case of monozygotic twin sisters with a clinical diagnosis of SRS, mild intellectual disability and epilepsy who carry a balanced translocation between chromosomes 3 and 12 that interrupts the NAALADL2 and HMGA2 genes, respectively. Disruption of HMGA2, a gene previously described as causative of SRS, confirms the initial diagnosis. NAALADL2 gene has been recently proposed as a candidate for intellectual disability and could partially contribute to our patient's phenotype.

An increasing number of patients utilizing in vitro fertilization (IVF) and assisted reproductive technology (ART) are characterized as impaired or poor ovarian responders (PORs). Owing to its unclear molecular etiology, the management of patients with age-related ovarian characteristics remains a controversial and complex clinical concern. Therefore, it is important to identify and understand the etiological causes behind POR to develop more effective and efficient management strategies for these patients. In this study, we report a homozygous HSD17B1 (accession number: NM_000413.4) variant (c.718-1G>C) in a patient with POR from a consanguineous family. The proband, a 33-years-old woman, exhibited poor ovarian reserve prestimulation parameters (antral follicle count < 5; anti-Müllerian hormone = 0.386 ng/mL), resulting in the classification of this patient as patient oriented strategies encompassing individualized oocyte number (POSEIDON) group three according to the POSEIDON criteria. Additionally, this patient displayed impaired estradiol production and reduced 17-ketosteroids secretion and multiple ovarian cysts, which differed from previously reported POR cases. Overall, our findings provide valuable insights for researchers and clinicians into the relationships between the phenotype and genotype of POR and the HSD17B1 gene.

Bainbridge-Ropers Syndrome (BRPS) is a genetic condition resulting from truncating variants in the ASXL3 gene. The clinical features include neurodevelopmental and language impairments, behavioral issues, hypotonia, feeding difficulties, and distinctive facial features. In this retrospective study, we analyzed 22 Spanish individuals with BRPS, aiming to perform a detailed clinical and molecular description and establish a genotype-phenotype correlation. We identified 19 ASXL3 variants, nine of which are novel. We documented recurrence in nontwin siblings due to parental mosaicism. The predominant prenatal finding was intrauterine growth restriction (35%) followed, after birth, by feeding difficulties (90.5%), hypotonia (85.7%), and gastroesophageal reflux disease (82.4%). Later in life, intellectual disability, language impairment, autism spectrum disorder (75%), and joint laxity (73.7%) were noted. Individuals with variants in the 3' mutational cluster region (MCR) of exon 12 exhibited more perinatal feeding problems, and those with variants in the 5' MCR of exon 11 displayed lower percentiles in height and occipitofrontal circumference, as well as higher frequency of arched eyebrows. This study is the first characterization of a Spanish BRPS cohort, with more than 50 clinical features analyzed, representing the most detailed phenotypic analysis to date.

Focal facial dermal dysplasia (FFDD) type IV is a rare inherited facial defect caused by biallelic variants in CYP26C1. This study reports two novel Belgian FFDD type IV cases, both homozygous for a recurrent CYP26C1 frameshift variant, with a common 700 kb haplotype, indicating a founder effect.

Split-hand/foot malformation syndrome (SHFM) is a congenital limb malformation that is both clinically and genetically heterogeneous. Variants in WNT10B are known to cause an autosomal recessive form of SHFM. Here, we report a patient born to unrelated parents who was found to be a compound heterozygote for missense variants in WNT10B: c.994C>T, p.(Arg332Trp) and c.638T>G, p.(Phe213Cys). The variants were identified using long-read PacBio sequencing, which enabled phasing and confirmed that they were located on different alleles. The maternally inherited variant p.(Arg332Trp) has been previously reported, whereas the paternally inherited variant p.(Phe213Cys) is novel and absent from the gnomAD database. Our findings highlight the utility of long-read haplotype phasing, which provides valuable insights in determining the biallelic nature of variants in recessive disorders when parental DNA samples are unavailable.