Nonsense variants of STAG2 result in distinct congenital anomalies.
Ontology highlight
ABSTRACT:
SUBMITTER: Aoi H
PROVIDER: S-EPMC7501222 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Nonsense variants of <i>STAG2</i> result in distinct congenital anomalies.
Aoi Hiromi H Lei Ming M Mizuguchi Takeshi T Nishioka Nobuko N Goto Tomohide T Miyama Sahoko S Suzuki Toshifumi T Iwama Kazuhiro K Uchiyama Yuri Y Mitsuhashi Satomi S Itakura Atsuo A Takeda Satoru S Matsumoto Naomichi N
Human genome variation 20200918
Herein, we report two female cases with novel nonsense mutations of <i>STAG2</i> at Xq25, encoding stromal antigen 2, a component of the cohesion complex. Exome analysis identified c.3097 C>T, p.(Arg1033*) in Case 1 (a fetus with multiple congenital anomalies) and c.2229 G>A, p.(Trp743*) in Case 2 (a 7-year-old girl with white matter hypoplasia and cleft palate). X inactivation was highly skewed in both cases. ...[more]
Similar Datasets
Project description:The cohesin complex is an evolutionarily conserved multi-subunit protein complex which regulates sister chromatid cohesion during mitosis and meiosis. Additionally, the cohesin complex regulates DNA replication, DNA repair, and transcription. The core of the complex consists of four subunits: SMC1A, SMC3, RAD21, and STAG1/2. Loss-of-function mutations in many of these proteins have been implicated in human developmental disorders collectively termed "cohesinopathies." Through clinical exome sequencing (CES) of an 8-year-old girl with a clinical history of global developmental delay, microcephaly, microtia with hearing loss, language delay, ADHD, and dysmorphic features, we describe a heterozygous de novo variant (c.205C>T; p.(Arg69*)) in the integral cohesin structural protein, STAG2. This variant is associated with decreased STAG2 protein expression. The analyses of metaphase spreads did not exhibit premature sister chromatid separation; however, delayed sister chromatid cohesion was observed. To further support the pathogenicity of STAG2 variants, we identified two additional female cases from the DECIPHER research database with mutations in STAG2 and phenotypes similar to our patient. Interestingly, the clinical features of these three cases are remarkably similar to those observed in other well-established cohesinopathies. Herein, we suggest that STAG2 is a dosage-sensitive gene and that heterozygous loss-of-function variants lead to a cohesinopathy.
| S-EPMC7033032 | biostudies-literature
Project description:BackgroundAutosomal recessive intellectual developmental disorder-3 is caused by homozygous or compound heterozygous mutations in the CC2D1A gene. The disorder is characterized by intellectual disability (ID) and autism spectrum disorder (ASD). To date, 39 patients from 17 families with CC2D1A -related disorders have been reported worldwide, in whom only six pathogenic or likely pathogenic loss-of-function variants and three variants of uncertain significance (VUS) in the CC2D1A gene have been identified in these patients.MethodsWe described a patient with ID from a non-consanguineous Chinese family and whole-exome sequencing (WES) was used to identify the causative gene.ResultsThe patient presented with severe ID and ASD, speech impairment, motor delay, hypotonia, slight facial anomalies, and finger deformities. Threatened abortion and abnormal fetal movements occurred during pregnancy with the proband but not his older healthy sister. WES analysis identified a homozygous nonsense variant, c.736C > T (p.Gln246Ter), in the CC2D1A gene. In addition, six novel likely pathogenic CC2D1A variants were identified by a retrospective review of the in-house database.ConclusionsThis study expands the genetic and clinical spectra of CC2D1A-associated disorders, and may aid in increasing awareness of this rare condition. Our findings have provided new insights into the clinical heterogeneity of the disease and further phenotype-genotype correlation, which could help to offer scope for more accurate genetic testing and counseling to affected families.
| S-EPMC10944275 | biostudies-literature
Project description:Equine Multiple Congenital Ocular Anomalies (MCOA) syndrome is a heritable eye disorder mainly affecting silver colored horses. Clinically, the disease manifests in two distinct classes depending on the horse genotype. Horses homozygous for the mutant allele present with a wide range of ocular defects, such as iris stromal hypoplasia, abnormal pectinate ligaments, megaloglobus, iridociliary cysts and cataracts. The phenotype of heterozygous horses is less severe and predominantly includes iridociliary cysts, which occasionally extend into the temporal retina. In order to determine the genetic cause of MCOA syndrome we sequenced the entire previously characterized 208 kilobase region on chromosome 6 in ten individuals; five MCOA affected horses from three different breeds, one horse with the intermediate Cyst phenotype and four unaffected controls from two different breeds. This was performed using Illumina TruSeq technology with paired-end reads. Through the systematic exclusion of all polymorphisms barring two SNPs in PMEL, a missense mutation previously reported to be associated with the silver coat colour and a non-conserved intronic SNP, we establish that this gene is responsible for MCOA syndrome. Our finding, together with recent advances that show aberrant protein function due to the coding mutation, suggests that the missense mutation is causative and has pleiotrophic effect, causing both the horse silver coat color and MCOA syndrome.
| S-EPMC3781063 | biostudies-literature
Project description:OBJECTIVE: Congenital hypothyroidism is characterized by inadequate thyroid hormone production in newborn infants. Many infants with CH have co-occurring congenital malformations. This is an investigation on the frequency and types of congenital anomalies in infants with congenital hypothyroidism born from May 2006-2010 in Hamadan, west province of Iran. METHODS: The Iranian neonatal screening program for congenital hypothyroidism was initiated in May 2005. This prospective descriptive study was conducted in infants diagnosed with congenital hypothyroidism being followed up in Pediatric Endocrinology Clinic of Besat Hospital, a tertiary care centre in Hamadan. Cases included all infants with congenital hypothyroidism diagnosed through newborn screening program or detected clinically. Anomalies were identified by clinical examination, echocardiography, and X-ray of the hip during the infant's first year of life. RESULTS: A total of 150 infants with biochemically confirmed primary congenital hypothyroidism (72 females and 78 males) were recruited during the period between May 2006-2010. Overall, 30 (20%) infants had associated congenital anomalies. The most common type of anomaly was Down syndrome. Seven infants (3.1%) had congenital cardiac anomalies such as: ASD (n=3), VSD (n=2), PS (n =1), PDA (n=1). Three children (2.6%) had developmental dysplasia of the hip (n=3). CONCLUSION: The overall frequency of Down syndrome, cardiac malformation and other birth defect was high in infants with CH. This reinforces the need to examine all infants with congenital hypothyroidism for the presence of associated congenital anomalies.
| S-EPMC3472568 | biostudies-other
Project description:BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.
| S-EPMC7785698 | biostudies-literature
Project description:Congenital anterior segment anomalies are disorders that affect the development of the eye and cause severe visual impairment. The molecular basis of congenital anterior segment anomalies is not well known. In this study, genome sequencing was performed on 27 families from diverse ethnicities with congenital anterior segment anomalies and 11 variants were identified, most of which were novel and family specific. These variants included single nucleotide variants CPAMD8:c.4825 C > T, c.534 G > A, CRYBB1:c.683 C > A, NHS:c.1180 C > T, GJA3:c.176 C > T, CRYGC:c.470 G > A, COL2A1:c.2819 G > A, c.1693 C > T, EPHA2:c.2864 A > C, a splice donor variant in COL11A1:c.933 + 1del, and a copy number variant in FBN1. The observed inheritance patterns were predominantly dominant, with a few recessive cases and a single instance of X-linked inheritance. Genome sequencing identified variants in 40.74% of diverse cases, offering valuable insights for enhancing the diagnosis and management of this disorder.
| S-EPMC11695809 | biostudies-literature
Project description:PAN2 encodes a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. A homozygous frameshift deletion in PAN2 was reported in a single affected individual with developmental delay and multiple congenital anomalies. Here, we describe five additional individuals from three unrelated families with homozygous predicted loss-of-function variants in PAN2. The affected individuals presented with significant overlap in their clinical features, including mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck. Our data confirm that biallelic predicted loss-of-function variants in PAN2 cause a syndrome with multiple congenital anomalies, and suggest an important role of mRNA polyA tail length for proper organ formation.
| S-EPMC9090724 | biostudies-literature
Project description:TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.
| S-EPMC6035372 | biostudies-literature
Project description:The PROM1 (prominin 1) gene encodes an 865-amino acid glycoprotein that is expressed in retinoblastoma cell lines and in the adult retina. The protein is localized to photoreceptor outer segment disc membranes, where it plays a structural role, and in the retinal pigment epithelium (RPE), where it acts as a cytosolic protein that mediates autophagy. Mutations in PROM1 are typically associated with cone-rod dystrophy 12 (OMIM#3612657), autosomal dominant retinal macular dystrophy 2 (OMIM#608051), autosomal recessive retinitis pigmentosa 41 (OMIM#612095), and Stargardt disease 4 (OMIM#603786). Here we describe the first case of PROM1-associated Leber congenital amaurosis (LCA) in a 12-yr-old Asian male, caused by two not previously described deleterious frameshift variants in the compound heterozygous state. Clinical features include the presence of bull's eye maculopathy, pendular horizontal nystagmus, and photodysphoria consistent with the clinical diagnosis of LCA. The patient was evaluated using ophthalmic imaging, electroretinography, and whole-exome sequencing. Electroretinography revealed extinguished retinal activity.
| S-EPMC6913139 | biostudies-literature
Project description:Background and objectiveImpact of appearance of congenital hand anomalies has not previously been reported. The purpose of this study was to describe the common perception about how different congenitally malformed hands look.MethodsWe developed a questionnaire in a game format to evaluate the appearance of different hands. Altogether 1450 (954 females) 4- to 84-year-old residents (296 children) of two European and one Asian (n = 102) country were asked to rate the appearance of different looking hands on a five-point pictorial Likert-type scale. Standardized photographs of the dorsal aspect of 17 different congenitally malformed non-operated hands and a normal hand were presented to respondents. Significance of age, gender, nationality, and profession of the respondents was assessed.ResultsThe respondents' ranking order of the hands was nearly consistent. The normal hand (mean = 4.43, standard deviation = 0.85, Md = 5) and clinodactyly (mean = 4.37, standard deviation = 0.86, Md = 5) were perceived to have the best appearance. Symbrachydactyly (mean = 1.42, standard deviation = 0.68, Md = 1) and radial club hand (mean = 1.40, standard deviation = 0.68, Md = 1) received the lowest scores. Adults rated the appearance of hands higher than children regarding 14 hands, females higher than men regarding 15 hands, and Europeans higher than Asians in 4 hands (p < 0.05, respectively). Europeans rated four-finger hand (mean = 3.21, standard deviation = 1.18, Md = 3) better looking than six-finger hand (mean = 2.92, standard deviation = 1.18, Md = 3, p < 0.005), whereas Asians gave higher scores to six-finger hand (mean = 2.66, standard deviation = 1.26, Md = 3) compared to four-finger hand (mean = 2.51, standard deviation = 1.14, Md = 2). Medical doctors and nurses gave higher scores compared to the other profession groups, school children, and high school students in five hands (p < 0.05).ConclusionsA normal hand is perceived distinctly better looking than most congenitally different hands. Different malformations' appearance was ranked very coherently in the same order despite of participants' age, gender, nationality, or profession. Asians seem to prefer an additional digit to a four-finger hand.
| S-EPMC8551435 | biostudies-literature