Congenital Anomalies最新文献

In Japan, a limited number of laboratories perform comprehensive genetic testing for rare diseases; this study investigated the attitudes of these laboratories toward the disclosure of secondary finding (SF). Following a preliminary survey, we identified laboratories conducting comprehensive genetic testing for participation. Subsequently, an online survey involving 20 selected facilities was conducted. The response rate was 80% (16/20). Of the 14 facilities, 71.4% had SFs. While 42.9% of them had a policy to disclose SFs with clinical utility, only 14.3% actively searched for actionable variants that could be included in the American College of Medical Genetics and Genomics list. Japan was less enthusiastic than the USA regarding SF disclosure. With regard to the reasons for not disclosing SFs, the factors “the thought that participants may have a low desire for SFs” and “uncertainty regarding their wish” were considered more important than in the USA. A content analysis of what was sought as a solution to this difficulty revealed a need to improve databases on pathogenicity and actionability and collect public thoughts on the issue. The factor “to promote entry in research” was not considered a critical reason for disclosing SFs, indicating that the thirst for information was not possibly due to anxiety but rather due to scientific interest. Japanese medical professionals may not be confident that society requires the disclosure of SFs. To improve the environment, it is necessary to survey the public regarding their thoughts on SF disclosure and discuss this issue in society.

Cleft lip and palate deformities substantially burden individuals and families, particularly in low-income communities. However, a comprehensive understanding of the patterns and distribution of these deformities in Kenya remains limited. This retrospective cross-sectional study analyzed 647 clinical records from the BelaRisu Foundation registry in Kenya, spanning 2018–2022. After meticulous record verification and data extraction, cleft pattern modeling was used to analyze each case. Data were imported to SPSS version 29.0 and descriptive statistics were calculated, which included means, ranges, frequencies, percentages, and standard deviations. Additionally, a comparative analysis between genders was conducted. The findings revealed a higher average age of presentation compared with previous studies in Kenya, along with a greater susceptibility of males to cleft lip and palate defects overall. Noteworthy disparities in case distribution across provinces were observed. Cleft lip emerged as the most observed primary defect, while palatal fistulae constituted the most frequent secondary defect. Interestingly, while some results aligned with global trends, others diverged significantly from the existing literature, warranting further exploration and investigation. These findings shed light on the unique patterns and distribution of cleft lip and palate deformities in Kenya, highlighting the need for targeted interventions and support systems.

The aim was to establish a specific and definite connection between non-syndromic orofacial cleft patients and associated congenital heart disease (CHD). Following PRISMA guidelines, selective databases were searched for data collection. Studies showing a definite association of CHD with orofacial cleft were included, and studies non-specific of the association of orofacial cleft with CHD were excluded. Data extraction criteria were study design, frequency of CHD in overall non-syndromic orofacial cleft and in specific cleft type, and most prevalent congenital cardiac anomaly. DerSimonian Laird random effects model was used to estimate the pooled proportion of CHD, along with corresponding 95% confidence intervals (CIs) for each measure. Publication bias was assessed using Fail-Safe N analysis and the Rosenthel approach. Of a total of 182 articles searched, only 30 studies were assessed. The overall pooled estimate of the proportion of CHD in total cleft lips/palates was 16% (95% CI: 13–19). The odds of developing CHD in cleft palates was 4.08 times more as compared to cleft lips with 95% CIs of 3.86–4.33, and 1.65 more as compared to cleft lips and palates both with 95% CI of 1.52–1.68. We affirm the upsurging prevalence of CHD in non-syndromic cleft children and vehemently propose that it is of utmost importance to inculcate it in practice and policy-making to screen all non-syndromic orofacial cleft children for congenital cardiac anomaly. This study was registered on PROSPERO (ID no. CRD42023391597) on February 24, 2023.

Angelman syndrome (AS, MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, profound developmental delay, movement or balance problems, an excessively cheerful disposition, and seizures. AS results from inadequate expression of the maternal UBE3A gene (MIM #601623), which encodes an E3 ligase in the ubiquitin-proteasome pathway. Here we present the case of two sisters with features consistent with AS who had negative methylation analyses. An autism/intellectual disability expanded panel revealed a maternally inherited novel UBE3A (NM_001354506.2) variant c.2443C>T p.(Pro815Ser) in both patients that was initially classified as a variant of uncertain significance. The patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC) to further investigate the variant. Additional data, including deep phenotyping, familial segregation analysis, and in silico studies, suggest that the variant is likely pathogenic. 3D modeling studies based on the available crystal structure revealed that the Pro815Ser variant can introduce more flexibility into the protein and alter its enzymatic activity. Recent literature confirms the pathogenic nature of the variant. Reanalysis of the UBE3A variant has heightened existing knowledge of AS and has offered this family an end to their diagnostic odyssey.

The phenotype of SCA patients are diversities, make prenatal counseling and parental decision-making following the prenatal diagnosis of SCA more complicated and challenging. NIPT has higher sensitivity and specificity in screening trisomy 21 syndrome, but the effectiveness of NIPT in detecting SCA is still controversial. This study is a large-scale retrospective cohort of positive SCA screened from unselected singleton pregnancies by non-invasive prenatal testing (NIPT) from a single prenatal center of a tertiary hospital. Clinical information, indications, diagnostic results, ultrasound findings, pregnancy determinations, and follow-up were reviewed and analyzed. 596 cases of SCA positive were screened out of 122 453, giving a positive detection rate of 0.49%. 510 cases (85.6%) conducted with amniocentesis to detect fetal chromosome, of which 236 were confirmed as true positive of SCA with PPV of 46.3% (236/510). Of the 236 cases confirmed as true positive SCA, 114 cases (48.3%)chose to terminate the pregnancy (93.0%, 65.3%, 15.4% and 10.9% for 45,X, 47,XXY, 47,XXX and 47,XYY, respectively), 122 cases (51.7%) elected to continue the pregnancy. In conclusions, NIPT as a first-tier routine method for screening autosomal aneuploidies, also could play an important role in screening SCA. Low-risk pregnant women are the main indication for the detection of SCA as NIPT test provides to non-selective population. For 47,XXX and 47,XYY with mild phenotype, couples would like to continue the pregnancy. But for 45,X and 47,XXY, parents apt to terminate pregnancy no matter ultrasound abnormalities were found or not.

To assess the risk of major birth defects after first-trimester exposure to carbocisteine and ambroxol during pregnancy, we conducted a prospective cohort study using counseling data for drug use during pregnancy provided by the Japan Drug Information Institute in Pregnancy and Toranomon Hospital. Counseling information, including drug usage and participants' demographic information, was collected between April 1988 and December 2017. Pregnancy outcome data, including major birth defects, were obtained using a questionnaire administered 1 month after delivery. The risks of major birth defects after first-trimester exposure to carbocisteine (n = 588) and ambroxol (n = 341) were compared with those of nonteratogenic drug use during the first trimester (n = 1525). The adjusted odds ratio (aORs) for major birth defects was calculated using a multiple logistic regression analysis adjusted for confounders. The incidence of major birth defects was 1.2% (7/588) and 2.1% (7/341) in the carbocisteine and ambroxol groups, respectively, which was comparable to the control group (26/1525, 1.7%). Results of multiple logistic regression demonstrated similar nonsignificant risks for both carbocisteine (aOR: 0.66, 95% confidence interval [CI]: 0.40–1.1, p = 0.11) and ambroxol (aOR: 1.1, 95% CI: 0.18–7.2, p = 0.88). No specific major birth defects were reported in the carbocisteine or ambroxol groups. This study demonstrated that carbocisteine and ambroxol exposure during the first trimester was not associated with an increased risk of major birth defects. These results could help in counseling for the use of these drugs during pregnancy and further alleviate anxiety in patients.

Germline APC pathogenic variants (PVs) are found in around 5%–10% of patients with hepatoblastoma.¹ Previous studies have shown conflicting opinion about the necessity of the routine genetic testing to identify germline APC PVs.¹ To date, candidates for genetic testing and appropriate analysis method remain unknown. Here, we experienced an infantile case of multiple hepatoblastomas with β-catenin positivity and identified a germline APC PV.

Our patient was the second child of healthy parents. His parents and elder brother, aged 3 years old, had no history of hepatoblastoma or adenomatous polyposis (Figure 1A). At the age of 1 year, he presented with abdominal distention and poor feeding. A huge mass was palpable in his upper right abdomen. The blood test showed high alpha-fetoprotein level (96,129 ng/mL, reference 10–50). Abdominal contrast-enhanced magnetic resonance imaging revealed three liver lesions, which size were almost 1.2 cm in S4 area, 13.0 cm in S5-6 area, and 3.0 cm in S7 area (Figure 1B,C). Multiple hepatoblastomas were diagnosed. No metastasis or vascular infiltrations were seen. After the chemotherapy, a right lobectomy was performed. Pathological examination of the resected main tumor showed a cord-like structure of small atypical cells, which is similar to the fetal liver cells, confirming hepatoblastoma. Immunohistochemistry staining showed positive β-catenin in the nuclei of tumor cells (Figure 1D). After obtaining written consent from the patient's parents for genetic testing, we performed next-generation sequencing in tumor samples and found a previously reported heterozygous nonsense variant, APC (NM_000038.6) c.3340C > T, p.Arg1114*.² This variant was also identified in the peripheral blood by Sanger sequencing. This variant was not identified in either parent (Figure 1A). We shared with his parents the following information: (i) this germline APC variant caused hepatoblastoma in our patient, (ii) due to the potential risk for additional hepatoblastoma, regular checkups were strongly recommended, (iii) our patient may develop a less severe type of adenomatous polyposis from adolescence,² and (iv) this germline APC variant may cause other diseases, including brain tumors and osteoma.

Multiple lesions in identical organs are common in patients with cancer predisposing genetic background. We speculate that multiple hepatoblastomas could be also suggestive of the presence of the germline PVs. We detected positive β-catenin immunostaining in the nuclei of tumor cells in our patient. Previous studies showed (i) in hepatoblastomas with β-catenin positivity, tumor-driving CTNNB1 or APC variants were found in a mutually exclusive nature, (ii) somatic activating CTNNB1 variants are found in 60%–80% of hepatoblastomas, while somatic APC PVs are rarely f

Cranial neural crest cells (NCCs) are critical for craniofacial development. The administration of valproic acid (VPA) to pregnant females causes craniofacial malformations in offspring. However, the in vivo influence of VPA on mammalian cranial NCCs remains unclear. In this study, we aimed to elucidate the developmental stage-specific effect of VPA on cranial NCCs through the administration of a single dose of VPA to pregnant rat females immediately prior to the formation of the cranial neural crest (NC). We performed whole-mount immunohistochemistry or in situ hybridization to examine localization changes of gene transcripts associated with the epithelial–mesenchymal transition of the cranial NC (i.e., cranial NCC formation) and cranial NCC migration. The results showed that Hoxa2 mRNA was abnormally detected and Sox9 mRNA expression was decreased in the midbrain–rhombomere (R) 1/2 NC, which forms cranial NCCs that migrate to the frontonasal mass (FNM) and branchial arch (BA) 1, through VPA administration, thus reducing the formation of SNAI2-positive NCCs. Hoxa2-positive NCCs were detected normally in BA2 and abnormally in FNM and BA1, which are normally Hox-free, implying VPA-induced abnormal cranial NCC migration. In vitro verification experiments using the whole embryo culture system revealed that midbrain–R4 NCC migration was abnormal. These results indicate that VPA reduces the formation/delamination of the midbrain–R1/2 NCCs in a developmental stage-specific manner and subsequently causes the abnormal migration of R4 NCCs, which suggests that the abnormal formation and migration of cranial NCCs contribute to the inhibition of axonal elongation in the trigeminal nerve and a reduction in head size.