X-linked Mental Retardation Syndrome Research Articles

Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families

BackgroundIntellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome.MethodsExome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing.ResultsIn an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family.ConclusionsThe investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Analysis of clinical features and ATRX gene variants in a Chinese pedigree affected with X-linked alpha thalassemia mental retardation (ATR-X) syndrome

To explore the clinical characteristics and genetic basis of two brothers featuring X-linked alpha thalassemia mental retardation (ATR-X) syndrome. An infant who had presented at the Qilu Children's Hospital in 2020 for unstable upright head and inability to roll over and his family were selected as the study subjects. The clinical features of the child and one of his brothers were summarized, and their genomic DNA was subjected to targeted capture and next generation sequencing (NGS). The brothers had presented with mental retardation and facial dysmorphisms. NGS revealed that they had both harbored a hemizygous c.5275C>A variant of the ATRX gene located on the X chromosome, which was inherited from their mother. The siblings were diagnosed with ATR-X syndrome. The discovery of the c.5275C>A variant has enriched the mutational spectrum of the ATRX gene.

Derivation of Induced Pluripotent Stem Cells Line (RCPCMi009-A-1) with Knockout of the <i>UBE2A</i> Gene by CRISPR/Cas9 Genome Editing

The deletions and mutations in the UBE2A gene cause X-linked mental retardation syndrome of Nascimento type first described in 2006 (Nascimento et al., 2006). To study the role of the UBE2A gene in neurodevelopment, we generated a human iPSC line with knockout of the UBE2A gene (RCPCMi009-A-1) using genome editing CRISPR/Cas9 technology. The knockout of the UBE2A gene was confirmed by Western blotting. The pluripotent state of the RCPCMi009-A-1 iPSCs line was confirmed by typical stem cell morphology, normal male karyotype maintenance, expression of pluripotency markers and the ability to differentiate into three germ layers.

Novel USP9X Mutation in A Lebanese Patient with Delay and Microcephaly: Case Report and Review of Literature

Introduction: USP9X gene is located on the X-chromosome and encodes for an enzyme that regulates important substrates involved in neuronal growth and development. Thus, rare USP9X mutations were identified as directly causative of neurodevelopmental disorders (NDDs) and Intellectual Disability (ID) in homozygous males and more rarely in heterozygous females. In males, USP9X variants have been linked to an X-linked mental retardation syndrome that includes; central nervous system (CNS) abnormalities (white matter disturbances, thin corpus callosum, widened ventricles, and cerebellar defects), global delay with significant alteration of speech, language and behavior, hypotonia, joint hypermobility, digital abnormalities, gastro-intestinal symptoms, visual system defects and dysmorphic facial features. Patient Data: We report the rare case of a 3 years old and 8 months male patient presenting with NDD, ID, speech delay, progressive aggressive behavioral changes and CNS abnormalities (microcephaly, left periventricular lesion). He was found to have a USP9X variant carrying a missense mutation: USP9X, c.1870A>T p.(Met624Leu) on Whole-Exome Sequencing (WES). Discussion: Our patient had most of the important features of the previously described X-linked mental retardation syndrome but some were absent such as dysmorphic features, digital or visual abnormalities and hypotonia. Microcephaly rather than macrocephaly was noted, which could be an additional potential CNS malformation, expanding the spectrum of phenotypic characteristics of the USP9X variants. No associated congenital anomalies were noted that are usually more common in female subjects. Conclusion: This is to our knowledge the first reported case of a USP9X variant in Lebanon. The clinical characteristics matched most of the previously described features in the literature. Microcephaly was a new clinical feature not previously described and could be a new possible phenotypic characteristic of the disease.

New heritable ATRX mutation identified by whole exome sequencing and review

BackgroundThe mutations in the ATRX gene have been shown to cause two types of disorders: inherited mutations lead to alpha thalassemia X-linked mental retardation (ATR-X) syndrome and acquired somatic mutations cause alpha thalassemia myelodysplastic syndrome (ATMDS). Here we report a case of ATRX gene mutation without completely features of ATR-X or ATMDS syndromes. Moreover we review previous reports of ATRX gene mutations in both ATR-X syndrome and ATMDS.MethodsAfter sample collection and DNA extraction, whole exome sequencing was performed using Illumina HiSeq PE150 apparatus. The results were confirmed using Sanger sequencing for the patients and his relatives. Literature review was performed based on the published data in Web of science, Science direct, Springer link and Pubmed databases.ResultsWe identified a hemizygous missense ATRX gene mutation (ATRX, c.2388A > C, p. K796N) as a new disease-causing variant in the patient, heterozygous situation for his mother and his father was hemizygous for wild type allele. The literatures of patients were reviewed regarding the ATR-X syndrome.ConclusionsAccording to previous findings, inherited ATRX mutations are associated with a broad spectrum of clinical presentations. Therefore a person with a mild α-thalassemia phenotype may also has mutation in ATRX gene. Accordingly, it is critical for geneticist and physicians to increase awareness in molecular diagnosis of α-thalassemia patients.

Generation of an iPSC line (SMCPGi001-A) from a patient with Bain type X-linked mental retardation syndrome carrying HNRNPH2 gene mutation

Bain type X-linked mental retardation syndrome is an X-linked dominant neurodevelopmental disorder characterized by psychomotor developmental delay and intellectual disability. The rare syndrome is caused by HNRNPH2 gene mutation. In this study, the iPSC cell line (SMCPGi001-A) was acquired by Sendai virus-mediated iPSC reprogramming from the peripheral blood mononuclear cells (PBMCs) obtained from a 1-year-old girl with de novo p.R206W mutation in the HNRNPH2 gene. The identification experiments of stemness and differentiation potential of three germ layers showed that the cell line had pluripotent stem cell characteristics and the potential of tridermal differentiation.

Heterogeneous Clinical Characteristics of Allan-Herndon-Dudley Syndrome with SLC16A2 Mutations

Purpose: The purpose of this study was to expand our understanding of phenotypic and genetic variation in Allan-Herndon-Dudley syndrome (AHDS), which is a rare X-linked mental retardation syndrome characterized by hypotonia, generalized spasticity, and moderate-to-severe psychomotor retardation. AHDS is caused by a mutation of solute carrier family 16 member 2 (SLC16A2), which encodes monocarboxylate transporter 8 (MCT8), the transporter of triiodothyronine (T3) into neurons. Methods: We enrolled nine patients with AHDS from unrelated families, except for two patients who were cousins, through a retrospective chart review. Clinical features, brain imaging, electroencephalograms, thyroid hormone profiles, and genetic data were reviewed retrospectively and compared with previously reported cases. Results: We found three novel and five previously reported pathogenic variants in nine patients from eight families. All patients presented with hypotonia, spasticity, severe developmental delay, and elevated serum T3 levels. Cataplexy, which is a previously unreported phenotype, was found in two patients with the same mutation. In our cohort, seizures were uncommon (n=1) but intractable. Conclusion: This study broadens the known phenotypic variations of AHDS, ranging from relatively mild global developmental delay to a severe form of encephalopathy with hypotonia, spasticity, and no acquisition of independent sitting. The syndromic classification or genetic etiology of global developmental delay is extremely heterogeneous; therefore, early clinical suspicion is challenging for clinicians. However, severe mental retardation with hypotonia, spasticity, and elevated serum T3 levels in male patients is a highly suspicious clinical clue for the early diagnosis of AHDS.

Induced pluripotent stem cells (iPSCs) derived from a renpenning syndrome patient with c.459_462delAGAG mutation in PQBP1 (PEIi001-A).

The Renpenning syndrome spectrum is a rare X-linked mental retardation syndrome characterized by intellectual disability, microcephaly, low stature, lean body and hypogonadism. Mutations in the polyglutamine tract binding protein 1 (PQBP1) locus are causative for disease. Here, we describe the generation of an iPSC line from a patient mutated in the polar amino acid-rich domain of PQBP1 resulting in a C-terminal truncated protein (c.459_462 delAGAG, type p.R153fs193X).

72. THE COUPLES’ CHOICES ON PREIMPLANTATION GENETIC TESTING FOR MONOGENIC AFTER GENETIC COUNSELING IN JAPAN

Introduction In Japan, preimplantation genetic testing for monogenic (PGT-M) can only be done under Japan Society of Obstetrics and Gynecology (JSOG) approval facility. Inside the approval facility, case has to get an approval from JSOG. Due to such strict condition, there are only 5 facilities that have experienced the PGT-M. Even to the genetic diseases that are subjects of PGT-M among other countries, it is not so in Japan and only limited to severe genetic diseases with onset at childhood. In this study, we will consider the issues of PGT-M in Japan from our genetic counseling and their subsequent decision by couples who wanted PGT-M at our clinic. Material & methods The subject is 31 couples who made reservation of consultation with our clinic for the purpose of PGT-M from August 2014. In order to obtain approval of PGT-M by JSOG, the couple need to receive genetic counseling not only at the PGT-M implementation facility but also at two different facilities. Results 21 couples out of 30 couples who received genetic counseling at our clinic wished to apply PGT-M to JSOG. A couple with a child with an Alpha-thalassemia X-linked mental retardation syndrome failed to undergo consultation for genetic counseling at our clinic because the condition of the child worsened. After genetic counseling at our clinic, seven couples did not want PGT-M. One couple with a child with congenital glycosylation disorder of glycosylation (type Ik) gave up PGT-M because it was difficult to attend our clinic with treatment of the affected child since it took more than 3 hours to our clinic. Four couples abandoned PGT-M because it takes a long time to approve. Also, in a couple with Myotonic dystrophy 1 male patient, the fact that they are not suited for PGT-M was not easily accepted and they had to be re-consulted by other facilities before they could accept the fact. The couple of congenital myopathy central core disease was selected for PGT-M because of adult onset disease. In other two couples, one couple applied for PGT-M at different facility, and the other has not yet been able to make the decision after genetic counseling. Conclusions Although there may be couples who want to take PGT-M, there are not enough facilities that have experienced the PGT-M in Japan. In addition, indication of PGT-M in Japan is severely limited to diseases in which symptoms that strongly disdain daily life are developed and the survival is dangerous before reaching adults. In the future, based on overseas adaptation criteria, Japan's adaptation criteria should be relaxed

Epileptic Encephalopathy, Myoclonus-Dystonia, and Premature Pubarche in Siblings with a Novel C-Terminal Truncating Mutation in ATRX Gene.

The X-linked alpha thalassemia mental retardation (ATR-X) syndrome is a genetic disorder caused by X-linked recessive mutations in ATRX gene, related to a wide spectrum of clinical manifestations, such as alpha thalassemia, developmental delay, genital abnormalities, and gastrointestinal disorders. Patients with ATR-X syndrome can suffer from different types of epileptic seizures, but a severe epileptic encephalopathy pattern has not been described to date. We describe, for the first time, two brothers with genetically confirmed ATR-X syndrome who presented with drug-resistant epileptic encephalopathy, with tonic and polimorphic seizures reported in the elder brother and epileptic spasms in the younger brother. Moreover, both brothers showed a peculiar movement disorder with myoclonus-dystonia, worsened during periods of distress or pain. These cases expand the clinical spectrum of ATR-X syndrome and open new opportunities for the molecular diagnosis of ATRX mutations in male patients with severe epileptic encephalopathies and movement disorders.

Molecular diagnosis and functional study of a pedigree affected with Lubs X-linked mental retardation syndrome

To explore the genetic basis for a pedigree affected with X-linked mental retardation. The proband was subjected to chromosomal karyotyping, FMR1 mutation testing and copy number variation analysis with a single nucleotide polymorphism microarray (SNP array). His family members were subjected to multiplex ligation-dependent probe amplification (MLPA) assaying. Expression of genes within the repeated region were analyzed. The proband had a normal chromosomal karyotype and normal number of CGG repeats within the FMR1 gene. SNP array identified a 370 kb duplication in Xq28 (ChrX: 153 027 633-153 398 515), which encompassed 14 genes including MECP2. The patient was diagnosed as Lubs X-linked mental retardation syndrome (MRXSL). MLPA confirmed the presence of copy number variation, its co-segregation with the disease, in addition with the carrier status of females. Genes from the duplicated region showed higher levels of expression (1.79 to 5.38 folds) within peripheral blood nucleated cells of the proband. The patients were diagnosed with MRXSL. The expression of affected genes was up-regulated due to the duplication. Genetic counseling and prenatal diagnosis may be provided based on the results.

A novel in-frame deletion of OPHN1 in a family with syndromic X-linked mental retardation

A novel in-frame deletion of OPHN1 in a family with syndromic X-linked mental retardation

Alpha-thalassemia mental retardation syndrome: A case report of two affected siblings

Alpha-thalassemia mental retardation syndrome is an X-linked mental retardation (MR) syndrome characterized by a recognizable facial appearance, infantile hypotonia and cryptorchidism. Although the presence of alpha-thalassemia facilitates the diagnosis, its absence does not exclude the diagnosis of this rare syndrome. We describe two siblings who presented with facial dysmorphism, MR and a four-generation pedigree that revealed an X-linked recessive inheritance pattern. Their red blood cell indices were within the normal range; however, hemoglobin H inclusions were detected following cresyl blue staining on their peripheral blood film. Mutational analysis revealed a point mutation C7156T that is predicted to have caused a premature termination within the alpha-thalassemia MR syndrome gene in both siblings. Confirmation of this mutation has facilitated the process of genetic counseling, carrier testing and prenatal diagnosis amongst female relatives in this family.

ARX and other single genes in X-linked mental retardation: revisiting a population-based study

It has been calculated that monogenic genes for Xlinked mental retardation (XLMR) account for <10% of male MR [1]. XLMR can be classified as syndromic, referring to conditions with distinct neurological, physical or biochemical abnormalities, or nonsyndromic (unspecified or nonspecific). More than 20 genes are known to be associated with syndromic XLMR [2] and 13 genes have so far been identified with nonsyndromic XLMR [3]. The most common XLMR condition, fragile X syndrome (FRAXA) due to mutation in the FMR1 gene, occurs in approximately 1 in 6000 males in various populations, or in 2–2.5% in cohorts of MR males [4]. Although the search for genes has been very active in recent years, mutations in a “major” causative gene underlying a larger proportion of unexplained XLMR remain to be identified. Recently, the identification of mutations in the Aristaless related homeobox gene (ARX) in syndromic as well as non syndromic conditions [5,6] created optimism that ARX could be a major gene in XLMR, particularly since the phenotypic range

PP03.15 – 2755: Clinical metabolomics reveals a novel plasma biomarker for Snyder Robinson syndrome (X-linked spermine synthase deficiency)

Objective Clinical metabolomics has emerged as a powerful tool to study metabolic perturbations in various diseases and to unravel novel biomarkers. In a monocenter study on metabolic-genetic research into epileptic encephalopathies, we applied untargeted metabolomics in parallel with exome sequencing in twin brothers with epileptic encephalopathy of unknown etiology. Genetic analysis confirmed Snyder-Robinson syndrome (SRS), a rare X-linked mental retardation syndrome. The underlying spermine synthase (SMS) deficiency affects polyamine metabolism and reduces intracellular spermine. So far, the diagnosis of SRS relied on a reduced spermine/spermidine ratio in lymphoblasts and/or sequencing of the SMS gene. Case The male monozygotic twins presented with developmental delay, progressive microcephaly and discrete dysmorphic features. From the age of 12 months, they developed therapy-resistant seizures with recurrent irregular myoclonic jerks and serial spasms in twin A. The EEG showed an abnormal background activity and multifocal and generalized spike waves. Additional atonic and tonic seizures and atypical absences occurred in both. At the age of 15 months, they developed a severe encephalopathy with frequent seizures, loss of milestones, impairment of visual interaction and a transient choreo-athetotic movement disorder. Both twins showed signs of osteopenia, twin B suffered a non-traumatic clavicular fraction at 23 months. Methods Clinical exome sequencing was applied in both twins and their parents. Sanger sequencing was applied to confirm the candidate variant. An untargeted plasma metabolomics analysis was performed by liquid chromatography–high-resolution mass spectrometry (LC-MS). Results Exome sequencing revealed a novel SMS missense mutation. Discriminant statistical analysis of the LC-MS data showed a distinct plasma metabolomics profile while comparative analysis versus age-matched controls revealed significantly elevated levels of N-acetylspermidine, a metabolite involved in spermine metabolism. Conclusion A combined clinical “omics” approach revealed N-acetylspermidine as a novel plasma biomarker for spermine synthase deficiency and identified a novel missense mutation in twin boys with SRS.

A Novel Plasma Biomarker for Snyder Robinson Syndrome (X-Linked Spermine Synthase Deficiency)

Background: Snyder-Robinson syndrome (SRS) is a rare X-linked mental retardation syndrome caused by mutations in the spermine synthase (SMS) gene. SMS dysfunction causes a reduction in intracellular spermine, a polyamine involved in various cellular processes. To date, the diagnosis of SRS relied on an elevated spermidine/spermine ratio in lymphoblasts and/or sequencing of the SMS gene.

Co-inheritance of novel ATRX gene mutation and globin (α & β) gene mutations in transfusion dependent beta-thalassemia patients.

α-Thalassemia X-linked mental retardation syndrome is a rare inherited intellectual disability disorder due to mutations in the ATRX gene. In our previous study of the prevalence of β-thalassemia mutations in the Eastern Province of Saudi Arabia, we confirmed the widespread coinheritance of α-thalassemia mutation. Some of these subjects have a family history of mental retardation, the cause of which is unknown. Therefore, we investigated the presence or absence of mutations in the ATRX gene in these patients. Three exons of the ATRX gene and their flanking regions were directly sequenced. Only four female transfusion dependent β-thalassemia patients were found to be carriers of a novel mutation in the ATRX gene. Two of the ATRX gene mutations, c.623delA and c.848T>C were present in patients homozygous for IVS I-5(G→C) and homozygous for Cd39(C → T) β-thalassemia mutation, respectively. While the other two that were located in the intronic region (flanking regions), were present in patients homozygous for Cd39(C → T) β-thalassemia mutation. The two subjects with the mutations in the coding region had family members with mental retardation, which suggests that the novel frame shift mutation and the missense mutation at coding region of ATRX gene are involved in ATRX syndrome.

Arx together with FoxA2, regulates Shh floor plate expression

Mutations in the Aristaless related homeodomain transcription factor (ARX) are associated with a diverse set of X-linked mental retardation and epilepsy syndromes in humans. Although most studies have been focused on its function in the forebrain, ARX is also expressed in other regions of the developing nervous system including the floor plate (FP) of the spinal cord where its function is incompletely understood. To investigate the role of Arx in the FP, we performed gain-of-function studies in the chick using in ovo electroporation, and loss-of-function studies in Arx-deficient mice. We have found that Arx, in conjunction with FoxA2, directly induces Sonic hedgehog (Shh) expression through binding to a Shh floor plate enhancer (SFPE2). We also observed that FoxA2 induces Arx through its transcriptional activation domain whereas Nkx2.2, induced by Shh, abolishes this induction. Our data support a feedback loop model for Arx function; through interactions with FoxA2, Arx positively regulates Shh expression in the FP, and Shh signaling in turn activates Nkx2.2, which suppresses Arx expression. Furthermore, our data are evidence that Arx plays a role as a context dependent transcriptional activator, rather than a primary inducer of Shh expression, potentially explaining how mutations in ARX are associated with diverse, and often subtle, defects.

Molecular studies on ARX gene in syndromic and non-syndromic mental retardation

Background Mental retardation (MR) is frequently the result of genetic mutations. Syndromic mental retardation is intellectual deficits associated with other medical and behavioral signs and symptoms. Non-syndromic mental retardation refers to intellectual deficits that appear without other abnormalities. The newly identified ARX (Aristaless related homeobox) gene consists of five exons and encodes 562 amino acid proteins and is thought to regulate brain development. Mutations in the ARX gene are associated with a diverse spectrum of phenotypes ranging from severe developmental abnormalities of the brain to syndromic and nonsyndromic forms of X-linked mental retardation (XLMR) syndromes that can be associated with normal or abnormal brain morphology. Mutations in the human ARX gene are the major cause of developmental and neurological disorders.

Opening the Black Box: Revealing the Molecular Basis of Thyroid Hormone Transport

The past 2 decades have seen a remarkable explosion of information about the structural basis of ligand interactions with nuclear hormone receptors. Hormones, however, do not simply interact with an isolated receptor but, rather, engage in transient interactions with many different proteins that comprise a system-wide hormone signaling pathway (1, 2). Thyroid hormones (THs), for example, bind to serum transport proteins that help to ensure even delivery of hormone to all tissues, cell type-specific membrane transporters, cytoplasmic interacting proteins, enzymes that variously activate prohormones or inactivate active hormones, and the TH receptors (TRs) themselves (3, 4). Presently, our understanding of chemical features of THs that are important for interactions with different binding proteins is incomplete. TH interacting proteins regulate important steps that dictate the availability of hormone for the intracellular receptor, so it is very important to understand structure activity relationships of TH in the context of both the receptor and the proteins that comprise the entire signaling system. Papers by Braun et al and Groeneweg et al in this issue of Endocrinology (23, 24) shed light on the molecular basis of cross-membrane TH transport by monocarboxylate transporter (MCT)8 (solute carrier family 16, member 2, SLC16A2). THs are zwitterionic amino acid derivatives. They have both positive and negative electrical charges and, therefore, require specific transporters in order to travel along concentration gradients across the hydrophobic plasma membrane (5, 6). It has traditionally been very difficult to directly investigate the organization of membrane proteins using classical structural biology approaches, and consequently, very little is known about the organization of TH transporters and the molecular basis of TH transport. Consideration of transporter function suggests that there must be overlaps and differences in ligand binding interactions relative to TRs. Both types of protein must display significant specificity for hormone (7, 8). The transporters, however,must transientlybindand then rapidly release hormone in a vectorial manner that stands in contrast to the requirement for a relatively stable hormone-receptor complex throughout the transcription cycle (9). Among known TH transporters, MCT8 is expressed in brain and liver and is highly selective for THs vs other molecules (10, 11). MCT8 is crucially important for uptake and efflux of THs across the blood-brain barrier and neurons and is the target for mutations that cause an inherited human disease called Allan-Herndon-Dudley syndrome (AHDS) (12). AHDS was one of the first reported X-linked mental retardation syndromes (13), and as yet, there is no treatment. ADHS males present with mental retardation, congenital hypotonia, and generalized muscle weakness. Additionally, there are characteristic alterations in TH homeostasis. Affected individuals exhibit high serum-free T3, low normal levels of free T4, and normal levels of TSH (14). Pathogenic MCT8 mutations have been described in more than 45 families worldwide and include frame-shifts, exon deletions, and nonsense and missense mutations, which all block activity of ectopically expressed MCT8 proteins in biochemical assays (15). Although the structure of MCT8 is not known, there are important clues about its organization and mechanism of action. First, MCT8 is a member of the large major facilitator superfamily of 12 transmembrane-spanning