High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations.
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ABSTRACT:
SUBMITTER: Reutter H
PROVIDER: S-EPMC9995338 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
Publications
High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations.
European journal of human genetics : EJHG 20230104 3
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Project description:Evidence suggests that genetic factors contribute to the development of anorectal malformations (ARMs). However, the etiology of the majority of ARMs cases remains unclear. Exome sequencing (ES) may be underutilized in the diagnostic workup of ARMs due to uncertainty regarding its diagnostic yield. In a clinical database of ~17,000 individuals referred for ES, we identified 130 individuals with syndromic ARMs. A definitive or probable diagnosis was made in 45 of these individuals for a diagnostic yield of 34.6% (45/130). The molecular diagnostic yield of individuals who initially met criteria for VACTERL association was lower than those who did not (26.8% vs 44.1%; p = 0.0437), suggesting that non-genetic factors may play an important role in this subset of syndromic ARM cases. Within this cohort, we identified two individuals who carried de novo pathogenic frameshift variants in ADNP, two individuals who were homozygous for pathogenic variants in BBS1, and single individuals who carried pathogenic or likely pathogenic variants in CREBBP, EP300, FANCC, KDM6A, SETD2, and SMARCA4. The association of these genes with ARMs was supported by previously published cases, and their similarity to known ARM genes as demonstrated using a machine learning algorithm. These data suggest that ES should be considered for all individuals with syndromic ARMs in whom a molecular diagnosis has not been made, and that ARMs represent a low penetrance phenotype associated with Helsmoortel-van der Aa syndrome, Bardet-Biedl syndrome 1, Rubinstein-Taybi syndromes 1 and 2, Fanconi anemia group C, Kabuki syndrome 2, SETD2-related disorders, and Coffin-Siris syndrome 4.
| S-EPMC9995493 | biostudies-literature
Project description:BackgroundCongenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.MethodsWe analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.ResultsAmong the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports.ConclusionWe conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and FOXP1-related disorders.
| S-EPMC8286264 | biostudies-literature
Project description:Background: A long list of syndromic entities can be diagnosed immediately through scrutinizing the clinical phenotype of the craniofacial features. The latter should be assisted via proper radiological interpretations. Patients and Methods: Different children aged from 1 month to 12 years were referred to our departments seeking orthopedic advice. Primarily, all received variable false diagnoses in other institutes. Two unrelated boys of one month and 12 months were falsely diagnosed as having positional plagiocephaly associated with contractures of idiopathic origin. Two unrelated boys of 14 months and 2 years were diagnosed with pseudo-hydrocephalus and non-specific syndrome, and were referred to explore their skeletal development. Two unrelated girls of 4 years old and 12 years old presented with multiple contractures were referred because of progressive scoliosis. A 4-year-old girl was referred with a false provisional diagnosis of facial diplegia. All children underwent detailed clinical, radiological and tomographic phenotypic characterizations and genetic testing, respectively. Results: Idaho syndrome (craniosynostosis associated with multiple dislocations) was the final diagnosis in the two unrelated boys with plagiocephaly and multiple contractures. Two children falsely diagnosed with pseudo-hydrocephalus and non-specific syndrome, were diagnosed with Silver-Russell syndrome (RSS). Contractural arachnodactyly Beals (CAB) was confirmed as the definitive diagnosis in the two unrelated girls with progressive scoliosis and multiple contractures. Parry-Romberg syndrome (PRS) associated with congenital lumbar kyphosis was the final diagnosis of the girl with the diagnosis of facial diplegia. Hypomethylation of ICR1 was confirmed in the RSS patients. Whole exome sequencing (WES) revealed a heterozygous mutation in the PRS patients. WES and array-CGH showed that no relevant variants or copy number variations (CNV) were identified in the CAB patients. Conclusions: On the one hand, newborn children can manifest diverse forms of abnormal craniofacial features, which are usually associated with either major or minor dysmorphic stigmata. A cleft lip/ palate is a major craniofacial malformation, and frontal bossing or a disproportionate craniofacial contour can be falsely considered as a transient plagiocephaly, which is spontaneously resolved by time. On the other hand, many physicians fall into the problem of deeming a countless number of diseases, such as contractures, as an idiopathic or non-specific syndrome. The latter stems from limited clinical experience. Therefore, failing to establish between the onset of the deformity and other inexplicit abnormal features that the patient or their immediate families or relatives carry is the final outcome. In this study, we used, for the first time, a reconstruction CT scan to further delineate the congenital disruption of the craniofacial anatomy and the other skeletal malformation complex.
| S-EPMC9600391 | biostudies-literature
Project description:Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to identify novel APVR genes. Based on data from this analysis, published case reports, mouse models, and/or similarity to known APVR genes as revealed by a machine learning algorithm, we identified 3 genes-EFTUD2, NAA15, and NKX2-1-for which there is sufficient evidence to support phenotypic expansion to include APVR. We also provide evidence that 3 recurrent copy number variants contribute to the development of APVR: proximal 1q21.1 microdeletions involving RBM8A and PDZK1, recurrent BP1-BP2 15q11.2 deletions, and central 22q11.2 deletions involving CRKL. Our results suggest that ES and chromosomal microarray analysis (or genome sequencing) should be considered for individuals with non-isolated APVR for whom a genetic etiology has not been identified, and that genetic testing to identify an independent genetic etiology of APVR is not warranted in individuals with EFTUD2-, NAA15-, and NKX2-1-related disorders.
| S-EPMC10689790 | biostudies-literature
Project description:Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.
| S-EPMC9669235 | biostudies-literature
Project description:PurposeA molecular diagnosis is only made in a subset of individuals with nonisolated microphthalmia, anophthalmia, and coloboma (MAC). This may be due to underutilization of clinical (whole) exome sequencing (cES) and an incomplete understanding of the genes that cause MAC. The purpose of this study is to determine the efficacy of cES in cases of nonisolated MAC and to identify new MAC phenotypic expansions.MethodsWe determined the efficacy of cES in 189 individuals with nonisolated MAC. We then used cES data, a validated machine learning algorithm, and previously published expression data, case reports, and animal models to determine which candidate genes were most likely to contribute to the development of MAC.ResultsWe found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189). Most genes affected in our cohort were not among genes currently screened in clinically available ophthalmologic gene panels. A subset of the genes implicated in our cohort had not been clearly associated with MAC. Our analyses revealed sufficient evidence to support low-penetrance MAC phenotypic expansions involving nine of these human disease genes.ConclusionsWe conclude that cES is an effective means of identifying a molecular diagnosis in individuals with nonisolated MAC and may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained. Our data also suggest that deleterious variants in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, and TUBA1A can contribute to the development of MAC.
| S-EPMC10959191 | biostudies-literature
Project description:ObjectiveAnorectal malformations (ARMs) are one of the commonest anomalies in neonates. Both laparoscopically assisted anorectal pull-through (LAARP) and posterior sagittal anorectoplasty (PSARP) can be used for the treatment of ARMs. The aim of this systematic review and meta-analysis is to compare these two approaches in terms of intraoperative and postoperative outcomes.MethodsMEDLINE, Embase, Web of Science and the Cochrane Library were searched from 2000 to August 2016. Both randomized and non-randomized studies, assessing LAARP and PSARP in pediatric patients with high/intermediate ARMs, were included. The primary outcome measures were operative time, length of hospital stay and total postoperative complications. The second outcome measures were rectal prolapse, anal stenosis, wound infection/dehiscence, anorectal manometry, Kelly's clinical score, and Krickenbeck classification. The quality of the randomized and non-randomized studies was assessed using the Cochrane Collaboration's Risk of Bias tool and Newcastle-Ottawa scale (NOS) respectively. The quality of evidence was assessed by GRADEpro.ResultsFrom 332 retrieved articles, 1, 1, and 8 of randomized control, prospective and retrospective studies, respectively, met the inclusion criteria. The randomized clinical trial was judged to be of low risk of bias, and the nine cohort studies were of moderate to high quality. 191 and 169 pediatric participants had undergone LAARP and PSARP, respectively. Shorter hospital stays, less wound infection/dehiscence, higher anal canal resting pressure, and a lower incidence of grade 2 or 3 constipation were obtained after LAARP compared with PSARP group values. Besides, the LAARP group had marginally less total postoperative complications. However, the result of operative time was inconclusive; meanwhile, there was no significant difference in rectal prolapse, anal stenosis, anorectal manometry, Kelly's clinical score and Krickenbeck classification.ConclusionFor pediatric patients with high/intermediate anorectal malformations, LAARP is a better option compared with PSARP. However, the quality of evidence was very low to moderate.
| S-EPMC5242536 | biostudies-literature
Project description:It remains controversial whether the distal rectal pouch should be either resected or used for reconstruction in anorectoplasty for the treatment of anorectal malformations (ARMs). Hence the aim of this study was to investigate whether ARMs were associated with a global neuromuscular maldevelopment of the terminal rectum specimens.There were 36 cases of ARMs (25 recto-bulbar fistula and 11 recto-prostatic fistula) and 10 healthy controls. The hematoxylin and eosin and Masson trichrome stain were used to conduct the histologic examination. The immunohistochemistry (IHC) and Western blot were conducted to analyze the neuron-specific enolase (NSE), S-100 protein, interstitial cells of Cajal marker (C-kit) within the rectal specimens in control group and ARM group.The most frequently observed histologic findings in mucosa were inflammation, congestion, eroded, and hemorrhage in the ARM cases. Submucosal inflammation and congestion were the most common submucosal findings in the ARM cases. Disrupted muscularis propria was observed in 60% of ARM cases. Mature ganglionic cells were reduced and muscularis propria showed reduced and patchy positivity for NSE, S-100, and C-kit protein in ARM group compared to that in control group according to IHC. Western blotting showed the expression levels of NSE, S-100, and C-kit were lower in the ARM group than that in the control group (P < .01).Histopathologic and IHC findings suggest that the distal rectal pouch has distinct defects in the neuromusculature. So it suggested that ARMs are abnormally developed tissue and need to be resected for better functional outcomes of the remaining gut.
| S-EPMC6081064 | biostudies-literature
Project description:RationaleDisruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected.ObjectivesTo provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions.MethodsClinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3).Measurements and main resultsCongenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions.ConclusionsThis study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K-AKT-mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.
| S-EPMC5955056 | biostudies-literature
Project description:Anorectal malformations are a common clinical problem affecting the development of the distal hindgut in infants. The spectrum of anorectal malformations ranges from the mildly stenotic anus to imperforate anus with a fistula between the urinary and intestinal tracts to the most severe form, persistent cloaca. The etiology, embryology, and pathogenesis of anorectal malformations are poorly understood and controversial. Sonic hedgehog (Shh) is an endoderm-derived signaling molecule that induces mesodermal gene expression in the chick hindgut. However, the role of Shh signaling in mammalian hindgut development is unknown. Here, we show that mutant mice with various defects in the Shh signaling pathway exhibit a spectrum of distal hindgut defects mimicking human anorectal malformations. Shh null-mutant mice display persistent cloaca. Mutant mice lacking Gli2 or Gli3, two zinc finger transcription factors involved in Shh signaling, respectively, exhibit imperforate anus with recto-urethral fistula and anal stenosis. Furthermore, persistent cloaca is also observed in Gli2(-/-);Gli3(+/-), Gli2(+/-);Gli3(-/-), and Gli2(-/-);Gli3(-/-) mice demonstrating a gene dose-dependent effect. Therefore, Shh signaling is essential for normal development of the distal hindgut in mice and mutations affecting Shh signaling produce a spectrum of anorectal malformations that may reveal new insights into their human disease equivalents.
| S-EPMC1850556 | biostudies-literature