Explore the vast range of titles available.

VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment.

A class of long non-coding RNA (lncRNA) with enhancer-like activity is found to associate with the co-activator complex Mediator and promote its genomic association and enzymatic activity; together with Mediator, the lncRNAs also help to maintain the chromosomal architecture of active regulatory elements. Mediator acts with ncRNA-a in gene regulation Long non-coding RNAs (lncRNAs) can both repress and activate gene expression. Here, a class of lncRNAs with enhancer-like activity is found to associate with the translational co-activator complex Mediator. Termed ncRNA-activating (ncRNA-a), these molecules promote the genomic association and enzymatic activity of Mediator, and acting together with Mediator, they also help to maintain the chromosomal architecture of active regulatory elements. Importantly, Mediator complexes containing disease-linked mutant MED12 proteins fail to associate with ncRNA-a. The MED12 gene encodes a Mediator complex subunit, and MED12 mutations have been linked to FG syndrome, a rare genetic disorder with symptoms including intellectual disability. This work suggests that the loss of Mediator–ncRNA-a interactions might be a possible contributing factor in such developmental diseases. Recent advances in genomic research have revealed the existence of a large number of transcripts devoid of protein-coding potential in multiple organisms 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Although the functional role for long non-coding RNAs (lncRNAs) has been best defined in epigenetic phenomena such as X-chromosome inactivation and imprinting, different classes of lncRNAs may have varied biological functions 8 , 9 , 10 , 11 , 12 , 13 . We and others have identified a class of lncRNAs, termed ncRNA-activating (ncRNA-a), that function to activate their neighbouring genes using a cis -mediated mechanism 5 , 14 , 15 , 16 . To define the precise mode by which such enhancer-like RNAs function, we depleted factors with known roles in transcriptional activation and assessed their role in RNA-dependent activation. Here we report that depletion of the components of the co-activator complex, Mediator, specifically and potently diminished the ncRNA-induced activation of transcription in a heterologous reporter assay using human HEK293 cells. In vivo , Mediator is recruited to ncRNA-a target genes and regulates their expression. We show that ncRNA-a interact with Mediator to regulate its chromatin localization and kinase activity towards histone H3 serine 10. The Mediator complex harbouring disease- 17 , 18 displays diminished ability to associate with activating ncRNAs. Chromosome conformation capture confirmed the presence of DNA looping between the ncRNA-a loci and its targets. Importantly, depletion of Mediator subunits or ncRNA-a reduced the chromatin looping between the two loci. Our results identify the human Mediator complex as the transducer of activating ncRNAs and highlight the importance of Mediator and activating ncRNA association in human disease.

Background Anorectal malformations (ARM) are rare forms of congenital uro-rectal anomalies with largely unknown causes. Besides genetic factors, prenatal exposures of the parents to nicotine, alcohol, caffeine, illicit drugs, occupational hazards, overweight/obesity and diabetes mellitus are suspected as environmental risk factors. Methods Relevant studies published until August 2010 were identified through systematic search in PubMed, EMBASE, ISI Web of Knowledge and the Cochrane Library databases. Furthermore, related and cross-referencing publications were reviewed. Pooled odds ratios (95% confidence intervals) were determined to quantify associations of maternal and paternal smoking, maternal alcohol consumption, underweight (body mass index [BMI] < 18.5), overweight (BMI 25-29.9), obesity (BMI ≥30) and maternal diabetes mellitus with ARM using meta-analyses. Results 22 studies that reported on the association between prenatal environmental risk factors and infants born with ARM were included in this review. These were conducted in the United States of America (n = 12), Spain (n = 2), Sweden (n = 2), the Netherlands (n = 2), Japan (n = 1), France (n = 1), Germany (n = 1) and Hungary (n = 1). However, only few of these studies reported on the same risk factors. Studies were heterogeneous with respect to case numbers, control types and adjustment for covariates. Consistently increased risks were observed for paternal smoking and maternal overweight, obesity and diabetes, but not for maternal smoking and alcohol consumption. In meta-analyses, pooled odds ratios (95% confidence intervals) for paternal smoking, maternal overweight, obesity, pre-gestational and gestational diabetes were 1.53 (1.04-2.26), 1.25 (1.07-1.47), 1.64 (1.35-2.00), 4.51 (2.55-7.97) and 1.81 (1.23-2.65), respectively. Conclusion Evidence on risk factors for ARM from epidemiological studies is still very limited. Nevertheless, the few available studies indicate paternal smoking and maternal overweight, obesity and diabetes to be associated with increased risks. Further, ideally large-scale multicentre and register-based studies are needed to clarify the role of key risk factors for the development of ARM.

In mammalian urorectal development, the urorectal septum (urs) descends from the ventral body wall to the cloaca membrane (cm) to partition the cloaca into urogenital sinus and rectum. Defective urs growth results in human congenital anorectal malformations (ARMs), and their pathogenic mechanisms are unclear. Recent studies only focused on the importance of urs mesenchyme proliferation, which is induced by endoderm-derived Sonic Hedgehog (Shh). Here, we showed that the programmed cell death of the apical urs and proximal cm endoderm is particularly crucial for the growth of urs during septation. The apoptotic endoderm was closely associated with the tempo-spatial expression of Wnt inhibitory factor 1 (Wif1), which is an inhibitor of Wnt- β -catenin signaling. In Wif1 lacZ/lacZ mutant mice and cultured urorectum with exogenous Wif1, cloaca septation was defective with undescended urs and hypospadias-like phenotypes, and such septation defects were also observed in Shh −/− mutants and in endodermal β-catenin gain-of-function (GOF) mutants. In addition, Wif1 and Shh were expressed in a complementary manner in the cloaca endoderm, and Wif1 was ectopically expressed in the urs and cm associated with excessive endodermal apoptosis and septation defects in Shh −/− mutants. Furthermore, apoptotic cells were markedly reduced in the endodermal β- catenin GOF mutant embryos, which counteracted the inhibitory effects of Wif1. Taken altogether, these data suggest that regulated expression of Wif1 is critical for the growth of the urs during cloaca septation. Hence, Wif1 governs cell apoptosis of urs endoderm by repressing β -catenin signal, which may facilitate the protrusion of the underlying proliferating mesenchymal cells towards the cm for cloaca septation. Dysregulation of this endodermal Shh-Wif1- β -catenin signaling axis contributes to ARM pathogenesis.

The cloaca is temporally formed and eventually divided by the urorectal septum (URS) during urogenital and anorectal organ development. Although congenital malformations, such as anorectal malformations (ARMs), are frequently observed during this process, the underlying pathogenic mechanisms remain unclear. β -Catenin is a critical component of canonical Wnt signaling and is essential for the regulation of cell differentiation and morphogenesis during embryogenesis. The expression of β -catenin is observed in endodermal epithelia, including URS epithelia. We modulated the β-catenin gene conditionally in endodermal epithelia by utilizing tamoxifen-inducible Cre driver line ( Shh CreERT2 ). Both β -catenin loss- and gain-of-function ( LOF and GOF ) mutants displayed abnormal clefts in the perineal region and hypoplastic elongation of the URS. The mutants also displayed reduced cell proliferation in the URS mesenchyme. In addition, the β-catenin GOF mutants displayed reduced apoptosis and subsequently increased apoptosis in the URS epithelium. This instability possibly resulted in reduced expression levels of differentiation markers, such as keratin 1 and filaggrin, in the perineal epithelia. The expression of bone morphogenetic protein ( Bmp ) genes, such as Bmp4 and Bmp7 , was also ectopically induced in the epithelia of the URS in the β-catenin GOF mutants. The expression of the Msx2 gene and phosphorylated-Smad1/5/8, possible readouts of Bmp signaling, was also increased in the mutants. Moreover, we introduced an additional mutation for a Bmp receptor gene: BmprIA . The Shh CreERT2/+ ; β-catenin flox(ex3)/+ ; BmprIA flox/− mutants displayed partial restoration of URS elongation compared with the β-catenin GOF mutants. These results indicate that some ARM phenotypes in the β-catenin GOF mutants were caused by abnormal Bmp signaling. The current analysis revealed the close relation of endodermal β -catenin signaling to the ARM phenotypes. These results are considered to shed light on the pathogenic mechanisms of human ARMs.

Background Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous studies have revealed that mutations in the SALL1 gene can disrupt normal development, resulting in the characteristic features of Townes-Brocks syndrome. Spalt-like transcription factors (SALLs) are highly conserved proteins that play important roles in various cellular processes, including embryonic development, cell differentiation, and cell survival. Over 400 different variants or mutations have been reported in the SALL1 gene in individuals with TBS. Most of these variants lead to the formation of premature termination codons (PTCs), also known as nonsense mutations. The majority of these PTCs occur in a specific region of the SALL1 gene called the “hotspot region”, which is particularly susceptible to mutation. Methods In this study, we conducted whole-exome sequencing on a three-generation Chinese family with anorectal malformations. Results We identified a novel heterozygous mutation (chr16:51175376:c.757 C > T p.Gln253*) in the SALL1 gene. Molecular analysis revealed a heterozygous C to T transition at nucleotide position 757 in exon 2 of the SALL1 (NM_002968) gene. This mutation is predicted to result in the substitution of the Gln253 codon with a premature stop codon (p.Gln253*). The glutamine-rich domain forms a long alpha helix, enabling the mutant protein to interact with the wild-type SALL1 protein. This interaction may result in steric hindrance effects on the wild-type SALL1 protein. Conclusions Our findings have expanded the mutation database of the SALL1 gene, which is significant for genetic counseling and clinical surveillance in the affected family. Furthermore, our study enhances the understanding of Townes-Brocks syndrome and has the potential to improve its diagnosis and treatment.

Background Townes-Brocks syndrome (TBS) is a rare autosomal dominant condition characterized by renal, anal, limb, and auditory abnormalities. TBS diagnosis can be challenging in settings where genetic analysis is not readily available. TBS traits overlap with those of Goldenhar and VACTERL syndromes. Case presentation Here, we present the case of a 5-year-old Brazilian boy born with an anorectal abnormality, limb and external ears malformations, genitourinary anomalies, and a congenital heart defect. Genetic analysis revealed a SALL1 nonsense mutation. The case is discussed in the context of the current literature. Conclusions Because of the variability in TBS clinical presentation, genetic analysis is key to the differential diagnosis of TBS relative to phenotypically similar syndromes.

Background Previous studies have revealed that mutations of Spalt Like Transcription Factor 1 ( SALL1 ) are responsible for Townes-Brocks syndrome (TBS), a rare genetic disorder that is characterized by an imperforate anus, dysplastic ears, thumb malformations and other abnormalities, such as hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. In addition, the protein tyrosine phosphatase receptor type Q ( PTPRQ ) gene has been identified in nonsyndromic hearing loss patients with autosomal recessive or autosomal dominant inherited patterns. Methods A Chinese family with TBS and hearing loss was enrolled in this study. The proband was a two-month-old girl who suffered from congenital anal atresia with rectal perineal fistula, ventricular septal defect, patent ductus arteriosus, pulmonary hypertension (PH), and finger deformities. The proband’s father also had external ear deformity with deafness, toe deformities and PH, although his anus was normal. Further investigation found that the proband’s mother presented nonsyndromic hearing loss, and the proband’s mother’s parents were consanguine married. Whole-exome sequencing and Sanger sequencing were applied to detect the genetic lesions of TBS and nonsyndromic hearing loss. Results Via whole-exome sequencing and Sanger sequencing of the proband and her mother, we identified a novel heterozygous mutation (ENST00000251020: c.1428_1429insT, p. K478QfsX38) of SALL1 in the proband and her father who presented TBS phenotypes, and we also detected a new homozygous mutation [ENST00000266688: c.1057_1057delC, p. L353SfsX8)] of PTPRQ in the proband’s mother and uncle, who suffered from nonsyndromic hearing loss. Both mutations were located in the conserved sites of the respective protein and were predicted to be deleterious by informatics analysis. Conclusions This study confirmed the diagnosis of TBS at the molecular level and expanded the spectrum of SALL1 mutations and PTPRQ mutations. Our study may contribute to the clinical management and genetic counselling of TBS and hearing loss.

BackgroundManitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described.Methods and resultsThis study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1bat/bat mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome.ConclusionsThe milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS–FREM complex diseases.

SALL1 heterozygous pathogenic variants cause Townes–Brocks syndrome (TBS), a condition with variable clinical presentation. The main features are a stenotic or imperforate anus, dysplastic ears, and thumb malformations, and other common concerns are hearing impairments, foot malformations, and renal and heart defects. Most of the pathogenic SALL1 variants are nonsense and frameshift, likely escaping nonsense-mediated mRNA decay and causing disease via a dominant-negative mechanism. Haploinsufficiency may result in mild phenotypes, but only four families with distinct SALL1 deletions have been reported to date, with a few more being of larger size and also affecting neighboring genes. We report on a family with autosomal dominant hearing impairment and mild anal and skeletal anomalies, in whom a novel 350 kb SALL1 deletion, spanning exon 1 and the upstream region, was identified by array comparative genomic hybridization. We review the clinical findings of known individuals with SALL1 deletions and point out that the overall phenotype is milder, especially when compared with individuals who carry the recurrent p.Arg276Ter mutation, but with a possible higher risk of developmental delay. Chromosomal microarray analysis is still a valuable tool in the identification of atypical/mild TBS cases, which are likely underestimated.