Clinical Genetics最新文献

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

The RAR-related orphan receptor alpha (RORA) gene encodes a nuclear receptor involved in transcriptional regulation, circadian rhythm, and neurodevelopment. Dominant RORA variants are associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia, yet the phenotypic spectrum remains poorly defined. We performed comprehensive genetic and clinical analyses in four individuals with RORA variants from three unrelated families, using whole exome sequencing and chromosomal microarray analysis. Identified variants were confirmed by Sanger sequencing. Genetic analyses revealed three distinct RORA variants: a 15q21.2-q22.2 deletion encompassing RORA, a de novo nonsense variant c.499C>T (p.Gln167*), and a novel heterozygous frameshift variant c.683_686del (p.Glu228Valfs*78) segregating within a family. Clinical findings ranged from severe neurodevelopmental delay and epilepsy to mild intellectual disability and behavioral abnormalities, demonstrating marked intrafamilial variability. Notably, the same frameshift variant presented with differing phenotypes in the family, indicating variable expressivity-the first such observation reported in RORA-related disorders. Our findings broaden the genotypic and phenotypic spectrum of RORA-related neurodevelopmental disorders. The observed intrafamilial variability highlights the complexity of RORA-associated pathogenesis and underscores the importance of considering variable expressivity in future genotype-phenotype studies.

This study aimed to analyze the clinical phenotypes, treatment response, and related risk factors in children with epilepsy to improve diagnosis and prognosis, employing a retrospective-prospective cohort design involving 848 children with non-acquired epilepsy who underwent genetic testing and were followed for 1-5 years to monitor treatment efficacy and development, with participants categorized into Gene-positive (n = 484) and Gene-negative (n = 364) groups for comparative analysis. Results showed that the Gene-negative group had a better treatment response than the Gene-positive group, and multivariate logistic analysis identified specific high-risk factors for poor treatment response in each group: febrile seizures history, delayed language development, concomitant congenital heart disease, and the use of ≥ 4 ASMs in the Gene-positive group, and comorbidities such as autism, intellectual disability, focal seizures, and multiple seizure types in the Gene-negative group. In conclusion, children with positive genetic findings exhibited more significant developmental delays/regression and poorer responses to treatment, underscoring the critical prognostic and therapeutic guidance value of genetic testing, while the treatment response observed at the 3-month mark serves as a significant predictor of long-term prognosis, offering a crucial reference for adjusting therapeutic strategies.

Noninvasive prenatal diagnosis relies on the analysis of the small amount of cell-free fetal DNA circulating in maternal plasma. Widely used to screen for chromosomal anomalies, the technique can also be applied to Mendelian diseases (NIPD-M). However, asserting the presence of a maternal variant in the fetus is challenging and requires the determination of the maternal haplotypes transmitted to the fetus. This is achieved via relative haplotype dosage (RHDO), a method that relies on the analysis of the allelic balance of multiple single-nucleotide polymorphisms around the pathogenic variant. An inherent risk of this method is that twin pregnancies and chromosomal anomalies like trisomy, monosomy or uniparental disomy unavoidably alter allelic balance, potentially leading to incorrect diagnosis. Here, we introduce an analytical method, fetal fraction signatures, that can detect such confounding situations in NIPD-M data, without the need for additional wet-lab work. We show that our method can reliably detect anomalies down to a low level of mosaicism and a low fetal fraction, thereby providing an essential quality-control tool for clinical testing by NIPD-M.

The RNA lariat debranching enzyme (DBR1) facilitates the hydrolysis of 2'-5' prime branched phosphodiester bonds. It acts on the bonds at the junction of excised lariat intron RNA, converting them into linear molecules for degradation. Mutations in the gene result in the accumulation of lariat introns, leading to multiple system dysfunction. This case involves two siblings who exhibited a homozygous gene mutation in DBR1, identified as the variant c.200A>G p.(Tyr67Cys). Both showed similar manifestations, including premature birth, intrauterine growth restriction, growth deficiency, ichthyosis, encephalopathy, respiratory symptoms, and death within 12-13 months of life, some of which were reported in the literature. Additionally, they showed novel phenotypes, including laryngomalacia, hypotonia, elevated intracranial pressure, and hypospadias. It is important to state that these siblings had another sibling with a heterozygous form and who is healthy, which supports the pathogenicity of the homozygous state. Adding to the association between this mutation and encephalitis, our patients were found to be additionally susceptible to respiratory tract infections. Although many patients with central nervous system disorders ultimately develop pulmonary infections, this is frequently a consequence of progressive neurological impairment, including compromised airway clearance. This paper enriches the existing literature and emphasizes the pathogenicity of the homozygous form.

This study is aimed at determining the spectrum of congenital heart disease associated with distal 22q11.22-23 deletions flanked by low copy repeats, LCR22 D-H. We analyzed cardiology findings in 128 unrelated individuals with distal LCR22 D-H deletions. A total of 62 were newly described and 66 were derived from previous reports. We found that deletions which included LCR22-D as the proximal endpoint were the most prevalent in the cohort (104/128, 81.3%). Clinically relevant congenital heart disease was identified in 48 individuals (37.5%, 95% CI 29%-46%), which is lower than the prevalence reported for typical, proximal LCR22 A-D deletions (p = 3.7E-4), especially for conotruncal defects (13/128, 10.2%; p = 7.1E-13). Mild to moderate CHD predominated, including ventricular septal defects (22/128), bicuspid aortic valve (9/128) and mild cardiomyopathy (3/128). Persistent truncus arteriosus was the most prevalent (n = 8/13) conotruncal heart defect, but other anomalies also occurred in singleton cases. These findings support the need for cardiac evaluation in all individuals with distal 22q11.22-23 deletions, increased use of clinical genetic testing in syndromic individuals with these findings, and molecular studies in model systems. The results demonstrate that reduced gene dosage of distal 22q11.21-23, particularly within the D-E region including MAPK1 and HIC2 convey risk for CHD.

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.

A patient of intellectual developmental disorder with autism and macrocephaly (IDDAM) caused by a novel CHD8 mutation developed adult-onset compulsive behaviors in addition to the core phenotype in early life. This case expands the clinical and genotypic spectrums of IDDAM which may inspire future studies on genotype-phenotype correlation and the disease course.

Pathogenic germline variants in DICER1 predispose to pleuropulmonary blastoma, multinodular goitre, embryonal rhabdomyosarcomas of the uterine cervix, ovarian Sertoli-Leydig cell tumour and a broader spectrum of pathologies. Here, we report a 35-year-old female with diagnoses of pineoblastoma, embryonal rhabdomyosarcoma, leiomyosarcoma, two meningiomas, and a germline DICER1 c.4206+1G>C, p.(?) variant. The variant was classified as a variant of unknown significance (VUS) based on the current ACMG/AMP gene-specific DICER1 guidelines. Additional functional analysis showed that the variant clearly abrogates the function of DICER1 and therefore PS3_Supporting evidence is included in the classification. Based on this the variant is reclassified as likely pathogenic. Moreover, our data suggest that the current ACMG/AMP gene-specific DICER1 guidelines should be modified in relation to the level of evidence strength (moderate to strong/very strong) for exon 22 skipping as well as to the use of the functional evidence (PS3) code.

FAM20B encodes glycosaminoglycan xylosylkinase, a key enzyme in proteoglycan biosynthesis. Biallelic pathogenic variants have only recently been linked to skeletal dysplasia. We report two pregnancies from one couple, resulting in three fetuses (twin sibs and younger sib) with severe skeletal anomalies. Prenatal findings included enlarged nuchal translucency, short bowed and dislocated limbs, intrauterine growth restriction, and multiple malformations. Intra-uterine fetal death occurred in Probands 1 and 2, and neonatal death of Proband 3. Postnatally, all three probands showed limb shortening with joint (sub)luxations and contractures, and craniofacial dysmorphisms. SNP-array and exome analysis revealed compound heterozygosity for two novel FAM20B variants: a paternal ~8 kb deletion encompassing the terminal exon and a maternal missense variant (p.Arg290Cys) at an evolutionary conserved position. The same amino acid residue was previously affected in a child with a milder phenotype. In silico modeling supports a destabilizing effect of the missense change on protein structure, especially due to the loss of a salt bridge essential for catalytic function. This report describes the prenatal phenotype of FAM20B-related dysplasia and can help establish the phenotypic spectrum of the disorder. It further supports the essential role of FAM20B in early skeletal development.