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Facial dysmorphism in ATRX syndrome-affected patients. (a)–(d) Patients with mutation in the helicase domain, (e) and (f) patients with mutation in the PHD-like domain. PHD, plant homeodomain.
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Mutations in ATRX are associated with a wide and clinically heterogeneous spectrum of X-linked mental retardation syndromes. The ATRX protein, involved in chromatin remodelling, belongs to the family of SWI/SNF DNA helicases and contains a plant homeodomain (PHD)-like domain. To date, more than 60 different mutations have been reported in ATRX. One...
Context in source publication
Context 1
... abnormalities were present in 16 patients, ranging from unilateral cryptorchidism to micropenis. Facial dysmorphism was constant and usually typical (Fig. 2), although mild in three cases. More rarely, other features were observed: one case of iris coloboma and one bifid thumb. A skewed pattern of X-inactivation was observed in all heterozygous carriers (n ¼ 14) in our series (Table ...
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The regulation of genome architecture is essential for a variety of fundamental cellular phenomena that underlie the complex orchestration of mammalian development. The ATP-dependent chromatin remodeling protein ATRX is emerging as a key regulatory component of nucleosomal dynamics and higher order chromatin conformation. Here we provide an overvie...
X-linked alpha thalassaemia mental retardation (ATR-X) syndrome in males is associated with profound developmental delay, facial dysmorphism, genital abnormalities and alpha thalassaemia. Female carriers are usually physically and intellectually normal. So far, 168 patients have been reported. Language is usually very limited. Seizures occur in abo...
Mutations in ATRX (alpha-thalassaemia and mental retardation on the X-chromosome) can give rise to ambiguous or female genitalia in XY males, implying a role for ATRX in testicular development. Studies on ATRX have mainly focused on its crucial role in brain development and α-globin regulation; however, little is known about its function in sexual...
In 2003, we described (1) a broad-range denaturing gradient gel electrophoresis method for mutation scanning of the entire open reading frame and canonical splice sites of the ATRX gene (OMIM 300032), a zinc finger transcriptional regulator undergoing X inactivation and probably involved in chromatin remodeling, DNA methylation, and gene expression...
Functional differentiation of chromatin structure is essential for the control of gene expression, nuclear architecture, and chromosome stability. Compelling evidence indicates that alterations in chromatin remodeling proteins play an important role in the pathogenesis of human disease. Among these, α-thalassemia mental retardation X-linked protein...
Citations
... The full-length ATRX and ATRXt isoforms both contain the HP1a and the EZH2 binding motifs, as well as the N-terminal ATRX-DNMT3-DNMT3L (ADD) domain, which comprises a GATA-like and a plant homeodomain (PHD) [9,12]. The great majority of the ATR-X syndrome-causing mutations are located within the ADD and the helicase domains [13,14]. ...
... Genotype-phenotype correlations have been proposed since the first reports of ATR-X syndrome. For instance, it has been suggested that a more severe psychomotor impairment is caused by variants affecting the PHD-like region of the ADD domain and that severe urogenital abnormalities are more frequent in cases where mutations are close to the C-terminus [13,14]. However, specific phenotypic differences related to specific ATRX protein domains are not well established and should not be used at this moment for prognostic purposes [6]. ...
... This was not surprising; this mutation is already known as the most common among ATR-X patients [13]. To the best of our knowledge, seven of the other variants have already been described [8,13,14,[26][27][28]. Of these, two different missense variants, the c.6253C > T and the c.6254G > A, involve the same amino acid residue, resulting in different substitutions (Table 1), as part of recurrent missense mutations of the ATRX residue 2085 [14,29]. ...
ATR-X syndrome is a rare X-linked congenital disorder caused by hypomorphic mutations in the ATRX gene. A typical phenotype is well defined, with cognitive impairment, characteristic facial dysmorphism, hypotonia, gastrointestinal, skeletal, urogenital, and hematological anomalies as characteristic features. With a few notable exceptions, general phenotypic differences related to specific ATRX protein domains are not well established and should not be used, at least at the present time, for prognostic purposes. The phenotypic spectrum and genotypic correlations are gradually broadening, mainly due to rapidly increasing accessibility to NGS. In this scenario, it is important to continue describing new patients, illustrating the mode and age of onset of the typical and non-typical features, the classical ones and those tentatively added more recently. This report of well-characterized and mostly unreported patients expands the ATR-X clinical spectrum and emphasizes the importance of better clinical delineation of the condition. We compare our findings to those of the largest ATR-X series reported so far, discussing possible explanations for the different drawn conclusions.
... However, the developmental consequences of PHD finger and helicase domain mutations are distinct. Mutations in the PHD finger are associated with severe intellectual disability and psychomotor impairment, while mutations in the helicase domain often manifest with milder neurodevelopmental delays but more severe genital abnormalities (25). This genotype-phenotype correlation suggests a more complex mechanism for disease than ATRX haploinsufficiency alone. ...
... ATRX mutations in the PHD finger and the helicase domains cause ATRX syndrome (25). To test if ATRX mutations affect neuronal differentiation in a mouse embryonic stem cell model, we characterized the effect of mutations in undifferentiated cells and upon differentiation into neural progenitors. ...
ATRX is a chromatin remodeler, which is mutated in ATRX syndrome, a neurodevelopmental disorder. ATRX mutations that alter histone binding or chromatin remodeling activities cluster in the PHD finger or the helicase domain respectively. Using engineered mouse embryonic stem cells that exclusively express ATRX protein with mutations in the PHD finger (PHDmut) or helicase domains (K1584R), we examine how specific ATRX mutations affect neurodifferentiation. ATRX PHDmut and K1584R proteins interact with the DAXX histone chaperone but show reduced localization to pericentromeres. Neurodifferentiation is both delayed and compromised in PHDmut and K1584R, and manifest differently from complete ATRX loss. We observe reduced enrichment of PHDmut protein to ATRX targets, while K1584R accumulates at these sites. Interestingly, ATRX mutations have distinct effects on the genome-wide localization of the polycomb repressive complex 2 (PRC2), with PHDmut and ATRX knockout showing reduced PRC2 binding at polycomb targets and K1584R showing loss at some sites and gains at others. Notably, each mutation associated with unique gene signatures, suggesting distinct pathways leading to impaired neurodifferentiation. Our results indicate that the histone binding and chromatin remodeling functions of ATRX play non-redundant roles in neurodevelopment, and when mutated lead to ATRX syndrome through separate regulatory pathways.
... The latter domain is involved in ATP-dependent RNA or DNA unwinding and its alterations are expected to alter the protein function. Mutations impairing the ATP-binding ability of the ATRX protein can impair its ability in chromatin remodeling during the cell cycle, thereby altering the expression of many downstream genes (Badens et al., 2006;Dyer et al., 2017). ...
Background: X-linked mental retardation-hypotonic facies syndrome-1
(MRXFH1), caused by a mutation in the ATRX gene, is a rare syndromic form
of X-linked mental retardation (XLMR) that is mainly characterized by severe
intellectual disability, dysmorphic facies, and skewed X-inactivation pattern in
carrier women.
Method: In this study, due to the genetic heterogeneity of the disease, we performed exome sequencing (ES) on a 15-year-old boy with primary microcephaly
and intellectual disability. Also, Sanger sequencing, cosegregation analysis, and
structural modeling were done to identify and verify the causative variant in the
proband and other affected individuals in the family. In addition, we collected
data from previously reported cases to compare with our patients' phenotypes.
Results: ES revealed a previously reported missense variant in the ATRX gene
(c.5182G>C, p.Ala1728Pro), segregating with the new clinical characteristic including primary microcephaly in the pedigree. This variant meets the criteria of
being likely pathogenic based on the ACMG variant interpretation guideline.
Conclusions: The findings of this study extend the spectrum of phenotypes
associated with the identified variant and provide further details on its clinical
features.
... encodes two transcripts, one of which encodes the full-length protein composed of 2,492 amino acids, while the other encodes a truncated protein generated by an alternative splicing event (7). The ATRX protein contains a zinc finger domain, which combines DNA and a helicase domain and functions in the transcription process to open double-stranded DNA (9). The ATRX protein belongs to the SWI/SNF2 family, which are ATP-dependent chromatin remodelers that play crucial roles in a broad range of biological functions such as transcriptional regulation, DNA repair and chromosome segregation (10). ...
Objective:
To analyze genetic mutations in a Chinese pedigree affected with Alpha-thalassemia X-linked intellectual disability syndrome, providing a precise diagnosis and genetic counseling.
Methods:
Clinical data was collected. A novel alternative splicing variant detected by whole-exome sequencing was validated by Sanger sequencing. The functional effect of the mutation was predicted with Mutation Tasting. The analysis of 5' splice site score was estimated with MaxEntScan. Changes in amino acid sequencing were predicted with Mutalyzer. The tertiary structures of the wild type and mutation-carrying protein were predicted by I-TASSER. RNA was extracted from peripheral blood lymphocytes from the proband, his mother and a healthy control. Quantitative Real-Time PCR was used to detect mRNA expression.
Results:
The proband presented with severe intellectual disability, developmental delay, characteristic facies, seizures and cryptorchidism. A novel hemizygous duplication mutation in the ATRX gene in a splice site between exons 3 and 4, NM_000489: c.189+1dupG, was identified with WES in the proband. Sanger sequencing confirmed that the mutation was inherited from his mother, who carried a heterozygous mutation, while his father was not affected. Bioinformatics analysis indicated that the splicing region where the mutation was located is highly conserved and the variant was damaging, producing a truncated protein due to the premature translation of a stop codon. Sanger sequencing with the Quantitative Real-Time PCR product containing a G base inserted between bases 189 and 190. The level of mRNA expression showed that ATRX gene transcription decreased due to the mutation (P < 0.05).
Conclusions:
A novel mutation in ATRX was found in this pedigree and was confirmed to be pathogenic through functional studies. Our research expanded the spectrum of ATRX gene mutations, providing a precise diagnosis and a basis for genetic counseling.
... 192 different germline mutations have been described in the ATRX gene (Table 3) (HGMD database). Most are point mutations, specifically missense, leading to reduced protein expression (Villard and Fontes 2002;Badens et al. 2006a). Deletions and duplications have also been reported in 6% of the cases (Thienpont et al. 2007;Gibbons et al. 2008;Lugtenberg et al. 2009, Cohn et al. 2009). ...
... Although no clear phenotypegenotype association has been reported for the most frequent clinical manifestations, all ATR-X syndrome patients with osteosarcoma reported to date carry mutations in the C-terminal region (Fig. 1B). Contrary to the data published by Badens et al. 2006a, b, our appraisal of published data suggests there is no difference in the severity of intellectual disability and severity of genital anomalies between mutations in the ADD and helicase domains (Badens et al. 2006a). ...
... Although no clear phenotypegenotype association has been reported for the most frequent clinical manifestations, all ATR-X syndrome patients with osteosarcoma reported to date carry mutations in the C-terminal region (Fig. 1B). Contrary to the data published by Badens et al. 2006a, b, our appraisal of published data suggests there is no difference in the severity of intellectual disability and severity of genital anomalies between mutations in the ADD and helicase domains (Badens et al. 2006a). ...
ATR-X, an acronym for alpha thalassemia and mental retardation X-linked, syndrome is a congenital condition predominantly affecting males, characterized by mild to severe intellectual disability, facial, skeletal, urogenital, and hematopoietic anomalies. Less common are heart defects, eye anomalies, renal abnormalities, and gastrointestinal dysfunction. ATR-X syndrome is caused by germline variants in the ATRX gene. Until recently, the diagnosis of the ATR-X syndrome had been guided by the classical clinical manifestations and confirmed by molecular techniques. However, our new systematic analysis shows that the only clinical sign shared by all affected individuals is intellectual disability, with the other manifestations varying even within the same family. More than 190 different germline ATRX mutations in some 200 patients have been analyzed. With improved and more frequent analysis by molecular technologies, more subtle deletions and insertions have been detected recently. Moreover, emerging technologies reveal non-classic phenotypes of ATR-X syndrome as well as the description of a new clinical feature, the development of osteosarcoma which suggests an increased cancer risk in ATR-X syndrome. This review will focus on the different types of inherited ATRX mutations and their relation to clinical features in the ATR-X syndrome. We will provide an update of the frequency of clinical manifestations, the affected organs, and the genotype–phenotype correlations. Finally, we propose a shift in the diagnosis of ATR-X patients, from a clinical diagnosis to a molecular-based approach. This may assist clinicians in patient management, risk assessment and genetic counseling.
... ATRX gene (OMIM 300032) is located in the Xq21.1 cytogenetic band, contains 36 exons and encodes an ATP-dependent helicase (XNP protein) belonging to the SNF2 superfamily that is involved in remodelling chromatin, DNA methylation and transcriptional regulation. This chromatin remodeler harbours two principal domains: ADD domain (exons 8-10) and helicase domain (exons [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] in which the majority of identi ed pathological mutations are located [5]. ADD domain, also called plant homeodomain (PHD)-like domain is in the N-terminal of the protein and it has a zinc nger-like structure. ...
... Therefore, it is considered a rare mutation. Thr1621Met is located in the helicase domain of the protein, which includes 17-30 exons [5;27] and is considered a 'hotspot' where 33% of sequence alterations are clustered [27]. This domain is the enzymatic core of the protein and plays an important role as a chromatin remodeler [8]. ...
... This novel mutation is also located in the helicase domain. We can hypothesize ATRX mutations in helicase domain might have an increased susceptibility to develop some sign of ASD while mutations in ADD domain are associated to a severe permanent psychomotor impairment and constant urogenital abnormalities [27]. To con rm this hypothesis, further genotype-phenotype relationship studies would be necessary in a large cohort of patients with ATRX mutations. ...
Background: ATRX gene mutations are commonly associated with alpha-thalassaemia mental retardation syndrome (ATRX syndrome). This X-linked disorder is characterized by intellectual disability to a higher or lesser degree, in which alpha-thalassaemia feature is not always present. Here, we report the first case of a Spanish child with a missense ATRX mutation (Thr1621Met) and an Autism Spectrum Disorder (ASD) diagnosis. Except for intellectual disability, no typical signs of ATRX syndrome were found in the patient.
Methods: A 23-month-old male patient was clinically evaluated at the Department of Paediatrics of the “Complejo Hospitalario Universitario de Albacete”, Spain. The baby was diagnosed with ASD according to the established criteria by the American Psychiatric Association (DMS-5). To determine the genetic cause of the pathology, an exome sequencing of a targeted gene panel of 215 genes associated to autism, intellectual disability, and/or seizure was carried out on an Ion Proton (Life Technologies) platform. The mutation was confirmed in the baby and analysed in the rest of the members of the family by PCR-terminator cycle sequencing.
Results: Thr1621Met ATRX hemizygous mutation was identified in the ASD patient. Proband´s mother was identified as an asymptomatic heterozygous carrier and the mutation was not found in the father neither the sister. Thr1621Met change is predicted to have a pathogenic effect and it has been previously associated with ATRX syndrome in only one German family with phenotypic variability.
Limitations: Given the limited number of families with ATRX mutations and, concretely, with Thr1621Met, it is very difficult to establish a genotype-phenotype relationship. Also, we cannot rule out the existence of other genetic, epigenetic and/or environmental factors that may modulate the phenotype of the patient. Furthermore, a functional analysis of Thr1621Met would be necessary to clarify the molecular mechanism by which this mutation causes ASD.
Conclusions: Results suggest one common altered molecular pathway in both, ATRX syndrome and ASD pathologies that opens new research lines in ASD aetiology. Furthermore, the results confirm the extent phenotypic variability associated with ATRX mutations and focus the attention on an exhaustive clinical examination to achieve the most accurate diagnosis.
... There are currently more than 150 putative disease-causing variants in ATRX, of which approximately a third are loss of function variants (frameshift, nonsense, splice site, gross deletions), while the majority of the remaining variants are missense variants (Gibbons & Higgs, 2000). Pathogenic variants located in the zinc finger domain of the ATRX protein have been reported to produce severe psychomotor impairment (Badens et al., 2006), whereas pathogenic variants in the helicase domains cause milder phenotypes (Gibbons & Higgs, 2000;Moncini et al., 2013). In general, the phenotype is characterized by distinctive craniofacial features, microcephaly, genital anomalies, skeletal anomalies, hypotonia, and ID that is typically severe to profound (Gibbons, 2006;Smith et al., 1980). ...
... Phenylalanine is a highly conserved amino acid and there is a physicochemical difference between phenylalanine and leucine. The observed missense variant is in Exon 8 in a functionally important domain which also is a mutation hotspot (Badens et al., 2006). All in silico tools utilized predict this variant to be damaging to protein structure and function. ...
... Otherwise, the clinical picture of ATRX-IDS has been largely described in the literature (Badens et al., 2006;Gibbons & Higgs, 2000); however, we found no description of a natural history up to middle age. ...
We have followed the clinical course of a 45‐year‐old man with a severe form of alpha‐thalassemia X‐linked intellectual disability syndrome for 40 years. The most challenging health issue is the combination of rumination, drooling, and vomiting. The patient achieved present adaptive and motor skills in his teenage years. He is able to move on the floor in a sitting position. He seems happy and has not shown any behavioral or psychiatric symptoms. New signs not described in the literature before are accelerated growth after puberty and atypical sleeping position with upper body resting on legs.
... The majority of ATR-X syndrome causing mutations are missense mutations mapping within the ADD (50%) and SNF2like/helicase domains (30%) (Argentaro et al., 2007;Gibbons et al., 2008). To date, there has been a lack of genotype: phenotype correlations identified, although mutations within the ADD domain typically produce more severe psychomotor phenotypes compared to mutations in the SNF2-like/helicase domain (Badens et al., 2006). ...
... Similarily, the Atrx E2 mice were smaller and also showed brain hypocellularity, although to a milder extent (Nogami et al., 2011). Atrx inactivation in Sertoli and muscle cells, also showed a significant impact on the growth of the tissue (Bagheri-fam et al., 2011;Huh et al., 2012). However, a retina progenitor cell cKO only had a limited effect on the size of the mature tissue suggesting that defects in cell cycle progression lead to significant hypocellularity among tissues that require a rapid expansion over a narrow developmental timeframe (Medina et al., 2009). ...
The ability to determine the genetic etiology of intellectual disability (ID) and neurodevelopmental disorders (NDD) has improved immensely over the last decade. One prevailing metric from these studies is the large percentage of genes encoding epigenetic regulators, including many members of the ATP-dependent chromatin remodeling enzyme family. Chromatin remodeling proteins can be subdivided into five classes that include SWI/SNF, ISWI, CHD, INO80, and ATRX. These proteins utilize the energy from ATP hydrolysis to alter nucleosome positioning and are implicated in many cellular processes. As such, defining their precise roles and contributions to brain development and disease pathogenesis has proven to be complex. In this review, we illustrate that complexity by reviewing the roles of ATRX on genome stability, replication, and transcriptional regulation and how these mechanisms provide key insight into the phenotype of ATR-X patients.
... One variant was pathogenic (c.6532C>T, p.Arg2178Trp, in 1 male patient; absent in the control group) and was previously reported to be pathogenic for alpha-thalassemia X-linked (ATR-X) intellectual disability syndrome in a patient with ATR-X syndrome who also developed osteosarcoma. 61,62 ...
... 48 Osteosarcoma has been reported in 5 children with the rare ATR-X genetic disorder, which is associated with heterozygous pathogenic germline variants in ATRX. 62,80,81 One of these previously reported patients with ATR-X syndrome developed osteosarcoma 61,62 and had a worse outcome, which is comparable with the osteosarcoma patient who had the same ATRX variant. ...
Importance
Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear.
Objective
To investigate the germline genetic architecture of 1244 patients with osteosarcoma.
Design, Setting, and Participants
Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019.
Main Outcomes and Measures
The frequency of rare pathogenic or likely pathogenic genetic variants.
Results
Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10⁻¹⁸). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53.
Conclusions and Relevance
In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.
... ATRX mutations can result in alterations in the pattern of ribosomal DNA methylation, Y-specific repeats and subtelomeric repeats (14,19,35), when the mutational 'hot-spots' occur in the cysteine-rich region and the aTPase/helicase-like motifs (36). However, patients with mutations in the PHd-like zinc finger present with more severe phenotypes compared with those that have mutations in the helicase domain (37). in addition to the expression of α-globin and an impaired intellectual level, mutated ATRX has been reported to be associated with various degrees of urogenital developmental disabilities (17). ...
... in conclusion, recently, more cases associated with mutations in ATRX have been identified on the basis of severe Mr with typical physical impairment (25,37). in the present study, since the family was relatively small and other family members did not exhibit similar phenotypes, it was difficult to clearly diagnose and identify the pathogenic gene; therefore, WeS followed by Sanger sequencing validation was adopted to detect the defective gene. consequently, a novel missense mutation was described that may have led to decreased aTrX activity in a chinese proband with SFMS, and which is available for the accurate diagnosis of other patients, laying the foundation for genetic counseling and prenatal diagnosis. ...
Smith‑Fineman‑Myers syndrome (SFMS) is a rare inherited disorder characterized mainly by mental retardation and anomalies in the appearance of patients. SFMS is caused by a mutation in the α‑thalassemia/mental retardation syndrome X‑linked (ATRX) gene and has an X‑linked recessive pattern. In the present study, a novel ATRX mutation was identified, and the association between its genotype and the phenotype was explored in a Chinese Han family with SFMS. This study aimed to lay a foundation for prenatal diagnosis for this family. Briefly, genomic DNA was extracted from peripheral blood samples obtained from the family. High‑throughput genetic sequencing was employed to detect the whole exome; subsequently, Sanger sequencing was performed to verify the candidate mutations. Clinical analysis of the proband was also accomplished. Consequently, a novel missense ATRX mutation was identified comprising a single nucleotide change of C to T, which caused an amino acid substitution at codon 172 in exon 7 (c.515C>T; p.Thr172Ile) of the proband. This mutation was found to co‑segregate in the present SFMS pedigree and was located in a highly conserved region of the ATRX protein, thus suggesting that it may be a pathogenic mutation. Taken together, these findings provided novel information that may lead towards an improved understanding of the genetic and clinical features of patients with SFMS, thereby facilitating a more accurate prenatal diagnosis of SFMS.
