Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of ...cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre. We excluded those with recognized syndromes, including 22q11.2 deletion syndrome. We identified candidate genes for TOF based on converging evidence between rare CNVs that overlapped the same gene in unrelated individuals and from pathway analyses comparing rare CNVs in TOF cases to those in epidemiologic controls. Even after excluding the 53 (10.7%) subjects with 22q11.2 deletions, we found that adults with TOF had a greater burden of large rare genic CNVs compared to controls (8.82% vs. 4.33%, p = 0.0117). Six loci showed evidence for recurrence in TOF or related congenital heart disease, including typical 1q21.1 duplications in four (1.18%) of 340 Caucasian probands. The rare CNVs implicated novel candidate genes of interest for TOF, including PLXNA2, a gene involved in semaphorin signaling. Independent pathway analyses highlighted developmental processes as potential contributors to the pathogenesis of TOF. These results indicate that individually rare CNVs are collectively significant contributors to the genetic burden of TOF. Further, the data provide new evidence for dosage sensitive genes in PLXNA2-semaphorin signaling and related developmental processes in human cardiovascular development, consistent with previous animal models.
Frontometaphyseal dysplasia (FMD) type 2 is an autosomal dominant disorder characterized by skeletal abnormalities and caused by MAP3K7 mutation. We identified a novel missense mutation in TAB2 ...associated with FMD in a child with multiple congenital malformations. This case was diagnosed as FMD due to joint contractures and bone deformities. This is the third report of FMD caused by a TAB2 mutation located in the TAK1-binding region.
Dyslexia is a reading disability characterized by difficulties with accurate and/or fluent word recognition, which are thought to stem from a phonological processing impairment. Herein we report the ...case of a 13-year-old girl who received the diagnosis of dyslexia at age 12 years. We considered this diagnosis to be incorrect because her reading difficulty was caused by a spontaneously repeated eye movement toward the vertical direction; the eyes were likely to show slow, upward drifts followed by quick downward movement at the physical examination, and the amplitude of the downward movement was increased when she changed eye positions to look at the upper direction in the evaluation of the eye tracker. Although we considered there was the possibility that the spontaneously repeated eye movement was classified as the spontaneous downbeat nystagmus, the eye tracker showed the transition of the gaze starting from and returning to was inconsistent with nystagmus, and we concluded that the term of nystagmus like abnormal eye movement was appropriate for the expression of the spontaneously repeated eye movement. There was no apparent abnormality on head magnetic resonance imaging (MRI), and whole exome sequencing showed no known candidate genes to explain the cerebellar dysfunction. An accumulation of similar cases in the future should help elucidate the pathomechanism observed in this case, and we should fully pay attention to evaluate the neurological aspects of the patients before settling on the diagnosis of dyslexia.
Purpose
Despite numerous studies, the etiology of spinal extradural arachnoid cyst (SEDAC), a lesion associated with neurological symptoms, remains unknown. In this genomic twin study, we ...investigated the genetic etiology of SEDACs.
Methods
The subjects were identical twins who developed notably similar SEDACs at the same vertebral level. Accordingly, we performed whole-exome sequencing analyses of genomic material from the twins and their parents using a next-generation sequencer. Additionally, we determined their detailed family history and analyzed the family pedigree.
Results
The pedigree analysis suggested the potential presence of SEDACs in certain family members, indicating a genetic disease. Sequenced data were analyzed and filtered using a purpose-built algorithm, leading to the identification of 155 novel single-nucleotide polymorphisms (SNPs), of which 118 encoded missense or nonsense variants. A functional analysis of the proteins encoded by these SNP alleles revealed strong enrichment for the fibronectin type III (FN3) protein domain (
q
= 0.00576). Specifically, the data indicated that a missense variant affecting the FN3 protein domain of fibronectin 1 (
FN1,
p.P969S) can be the causal mutation underlying the SEDACs.
Conclusion
The data suggest that deleterious mutations in fibronectin-related genes may cause SEDACs. In particular, it was suspected that a variant of
FN1
may be the cause of the SEDACs in the twin cases studied herein. Detailed studies with a larger number of cases are needed.
To avoid hemolytic disease of the fetus and newborn resulting from maternal alloantibodies against fetal Rh antigens, anti-D immunoglobulin is routinely administered to RhD-negative pregnant women in ...Japan. Fetal
genotyping using cell-free DNA may prevent unnecessary antibody administration; however, current PCR-based methods, which detect
deletion, do not address the higher rates of
-positive D antigen-negative alleles in nonwhite populations without additional inspections.
We developed an amplicon-sequencing method that could estimate the type of paternally inherited fetal
allele from 4 major
alleles in the Japanese population: the D antigen-positive allele (
*
, 92.9%) and 3 D antigen-negative alleles (
*
, 6.6%;
*
, 0.3%;
*
, 0.1%) using cell-free DNA obtained from the blood plasma of pregnant women.
The method correctly determined the fetal RhD type even when RhD-negative pregnant women possessed an
-positive D antigen-negative allele:
*
or
*
.
This method is a reliable noninvasive fetal
genotyping method for Japanese and other East Asian populations. The genotyping principle of amplifying 2 different regions using the same primer pair and distinguishing them by their sequence difference during the subsequent mapping procedure is also theoretically applicable to
-positive D antigen-negative alleles prevalent in Africans. Therefore, this method offers an opportunity to consider targeted administration of anti-D immunoglobulin to RhD-negative pregnant women in East Asian and African countries and to increase the specificity of the fetal
genotyping implemented nationwide in several European countries.
ST3GAL5 encodes GM3 synthase (ST3 beta-galactoside alpha-2,3-sialyltransferase 5; ST3GAL5), which synthesizes GM3 by transferring sialic acid to lactosylceramide. GM3, a sialic acid-containing ...glycosphingolipid known as ganglioside, is a precursor to the biosynthesis of various more complex gangliosides that are active in the brain. Biallelic variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD), a rare congenital disorder of glycosylation. GM3SD was first identified in the Amish population in 2004.
We report two siblings diagnosed with GM3SD due to novel compound heterozygous ST3GAL5 variants. The novel ST3GAL5 variants, detected by whole-exome sequencing in the patients, were confirmed to be pathogenic by GM3 synthase assay. The clinical courses of these patients, which began in infancy with irritability and growth failure, followed by developmental delay and hearing loss, were consistent with previous case reports of GM3SD. The older sibling underwent deep brain stimulation for severe involuntary movements at the age of 9 years. The younger sibling suffered from acute encephalopathy at the age of 9 months and subsequently developed refractory epilepsy.
Reports of GM3SD outside the Amish population are rare, and whole-exome sequencing may be required to diagnose GM3SD in non-Amish patients. Since an effective treatment for GM3SD has not yet been established, we might select deep brain stimulation as a symptomatic treatment for involuntary movements in GM3SD.
Ankyloblepharon-ectodermal defect-cleft lip/palate syndrome and Rapp-Hodgkin syndrome are well-known TP63-related autosomal-dominant genetic disorders with various similar ectodermal dysplasias. In ...this study, whole-exome sequencing revealed a novel, potentially pathogenic TP63 nonsense variant (NM_001114980.2:c.25 C > T: p.Gln9Ter) in a patient with an atypical clinical phenotype. This variant was detected near translation initiation sites and has an effect only on ΔNp63α, the short isoform protein product of the TP63 gene.
Otopalatodigital spectrum disorder (OPDSD) is characterized by variable phenotypes, including skeletal dysplasia, and is caused by pathogenic variants in filamin A-encoding FLNA. FLNA variants ...associated with lethal OPDSD primarily alter the CH2 subdomain of the ABD of FLNA. Herein, we report a novel FLNA mutation in a fetus with severe skeletal dysplasia in a pregnant multigravida female with a history of repeated miscarriages and terminations.
Fabry disease is a congenital lysosomal storage disease, and most of these cases develop organ damage in middle age. There are some promising therapeutic options for this disorder, which can ...stabilize the progression of the disease. However, a long delay in diagnosis prevents early intervention, resulting in treatment failure. Because Fabry disease is a rare disease, it is not well recognized and disease specific screening tests are rarely performed. Hence, a novel approach to for detecting patients with a widely practiced clinical test is crucial for the early detection of the disease. Recently, decision support systems based on artificial intelligence (AI) have been developed in many clinical fields. However, the construction of these models requires datasets from a large number of samples; this aspect is one of the main obstacles in AI-based approaches for rare diseases. In this study, with a novel image amplification method to construct the dataset for AI-model training, we built the deep neural-network model to detect Fabry cases from their urine samples. Sensitivity, specificity, and the AUC of the models on validation dataset were 0.902 (95% CI, 0.900–0.903), 0.977 (0.950–0.980), and 0.968 (0.964–0.972), respectively. This model could also extract disease-specific findings that are interpretable with human recognition. These results indicate that we can apply novel AI models for rare diseases based on this image amplification method we developed. We expect this approach could contribute to the diagnosis of Fabry disease.
This is the first reported AI-based decision support system to detect undiagnosed Fabry cases, and our new image amplification method will contribute to the AI models for other rare disorders.
Some monogenic inflammatory bowel diseases (IBDs) are known to be refractory to conventional treatments. Although allogeneic hematopoietic stem-cell transplantation (allo-HSCT) has become a curative ...therapeutic option for certain monogenic IBDs, its effectiveness regarding endoscopic improvements has not been clarified.
The clinical course and endoscopic findings of patients with monogenic IBDs who were treated with allo-HSCT between December 2017 and November 2018 at the National Center for Child Health and Development, were retrospectively reviewed. The clinical disease activity was assessed using the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) and the endoscopic finding was evaluated using the Simple Endoscopic Score for Crohn's Disease (SES-CD). Clinical remission was defined as a wPCDAI <10 and endoscopic remission was defined as an SES-CD of 2 or less.
Four patients with severe monogenic IBDs, including three with X-linked inhibitors of apoptosis protein (XIAP) deficiency and one with interleukin-10 signaling defect, were treated with allo-HSCT with reduced-intensity conditioning. In four patients, the maximum scores of wPCDAI and SES-CD before allo-HSCT ranged from 67.5 to 120 and 20 to 34, respectively. After allo-HSCT, all four patients showed a significant improvement in intestinal inflammation and achieved both clinical and endoscopic remission. Although patients with XIAP deficiency presented with post-transplant hemophagocytic lymphohistiocytosis and a relatively late engraftment, all patients achieved prolonged clinical remission, and IBD medications were successfully discontinued in all patients.
Allo-HSCT for monogenic IBD resulted in complete clinical resolution with endoscopically confirmed mucosal healing.
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