Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.     

A cryptic microdeletion including MBD5 occurring within the breakpoint of a reciprocal translocation between chromosomes 2 and 5 in a patient with developmental delay and obesity

The 2q23.1 deletion syndrome has been recently recognized as a neurodevelopmental disorder associated with intellectual disability, epilepsy, and autism spectrum disorder. Recently, methyl‐CpG‐binding domain 5 gene (MBD5), located in the 2q23.1 region, has been considered as a single causative gene of this syndrome. We report on a female patient with a de novo reciprocal translocation between chromosomes 2 and 5. Chromosomal microarray testing revealed a cryptic 896 kb deletion that included MBD5. Although clinical manifestations of this patient are compatible with those of patients with 2q23.1 deletion syndrome, a focal pachygyria revealed by brain magnetic resonance imaging has never been observed in the previously reported cases. Obesity caused by hyperphagia was observed in our patient and 28% of the previously reported patients with the 2q23.1 deletion syndrome. For better medical management, appropriate dietary guidance against hyperphagia should be given to the patients' family. © 2013 Wiley Periodicals, Inc.     

Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND)

MBD5-associated neurodevelopmental disorder (MAND) is an umbrella term that describes a group of disorders, 2q23.1 deletion syndrome, 2q23.1 duplication syndrome, and MBD5 variants, that affect the function of methyl-binding domain 5 (MBD5) and share a common set of neurodevelopmental, cognitive, and behavioral impairments. This review provides a comprehensive clinical and molecular synopsis of 2q23.1 deletion syndrome. Approaches to diagnosis, genetic counseling, and up-to-date management are summarized, followed by a discussion of the molecular and functional role of MBD5. Finally, we also include a brief summary of MBD5 variants that affect function of MBD5 and 2q23.1 duplication syndrome.     

Mutations in TBR1 gene leads to cortical malformations and intellectual disability

The advent of next generation sequencing has improved gene discovery in neurodevelopmental disorders. A greater understanding of the genetic basis of these disorders has expanded the spectrum of pathogenic genes, thus enhancing diagnosis and therapeutic management. Genetic overlap between distinct neurodevelopmental disorders has also been revealed, which can make determining a strict genotype-phenotype correlation more difficult. Intellectual disability and cortical malformations are two neurodevelopmental disorders particularly confronted by this difficulty. Indeed, for a given pathogenic gene, intellectual disability can be associated, or not, with cortical malformations. Here, we report for the first time, two individuals with the same de novo mutation in TBR1, leading to a frameshift starting at codon Thr532, and resulting in a premature stop codon 143 amino acids downstream (c.1588_1594dup, p.(Thr532Argfs*144)). These individuals presented with a developmental encephalopathy characterized by frontal pachygyria and severe intellectual disability. Remarkably, 11 TBR1 gene mutations were previously reported in intellectual disability and autism spectrum disorders. Our study supports the observation that TBR1-related disorders range from intellectual disability to frontal pachygyria. We also highlight the need for first-line, good quality neuroimaging for patients with intellectual disability.     

Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures

Microdeletion of chromosome 2q23.1 results in a novel syndrome previously reported in five individuals. Many of the del(2)(q23.1) cases were thought to have other syndromes such as Angelman, Prader–Willi, or Smith–Magenis because of certain overlapping clinical features. We report two new cases of the 2q23.1 microdeletion syndrome, describe the syndrome phenotype, define the minimal critical region, and analyze the expression of critical region genes toward identification of the causative gene(s) for the disorder. Individuals with del(2)(q23.1) have severe developmental and cognitive delays, minimal speech, seizures, microcephaly, mild craniofacial dysmorphism, behavioral disorders, and short stature. The deletions encompassing 2q23.1 range from >4 Mb to <200 kb, as identified by oligonucleotide and BAC whole-genome array comparative hybridization. The minimal critical region includes a single gene, MBD5, deleted in all cases, whereas all but one case also include deletion of EPC2. Quantitative real-time PCR of patient lymphoblasts/lymphocytes showed an ∼50% reduced expression of MBD5 and EPC2 compared with controls. With similar phenotypes among the 2q23.1 deletion patients, the idea of one or more common genes causing the pathological defect seen in these patients becomes evident. As all five previous cases and the two cases in this report share one common gene, MBD5, we strongly suspect that haploinsufficiency of MBD5 causes most of the features observed in this syndrome.     

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

Individuals with autism spectrum disorders (ASD) who have an identifiable single-gene neurodevelopmental disorder (NDD), such as fragile X syndrome (FXS, FMR1), Smith–Magenis syndrome (SMS, RAI1), or 2q23.1 deletion syndrome (del 2q23.1, MBD5) share phenotypic features, including a high prevalence of sleep disturbance. We describe the circadian deficits in del 2q23.1 through caregiver surveys in which we identify several frequent sleep anomalies, including night/early awakenings, coughing/snoring loudly, and difficulty falling asleep. We couple these findings with studies on the molecular analysis of the circadian deficits associated with haploinsufficiency of MBD5 in which circadian gene mRNA levels of NR1D2, PER1, PER2, and PER3 were altered in del 2q23.1 lymphoblastoid cell lines (LCLs), signifying that haploinsufficiency of MBD5 can result in dysregulation of circadian rhythm gene expression. These findings were further supported by expression microarrays of MBD5 siRNA knockdown cells that showed significantly altered expression of additional circadian rhythm signaling pathway genes. Based on the common sleep phenotypes observed in del 2q23.1, SMS, and FXS patients, we explored the possibility that MBD5, RAI1, and FMR1 function in overlapping circadian rhythm pathways. Bioinformatic analysis identified conserved putative E boxes in MBD5 and RAI1, and expression levels of NR1D2 and CRY2 were significantly reduced in patient LCLs. Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. These data support phenotypic and molecular overlaps across these syndromes that may be exploited to provide therapeutic intervention for multiple disorders.     

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature

PurposeRecurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined.MethodsWe systematically compiled all cases of 15q13.3 deletion published before 2014. We also examined three locally available cohorts to identify new adults with 15q13.3 deletions.ResultsWe identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4–BP5) region, including seven novel adult cases from local cohorts. No BP4–BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin (P < 0.0001). Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases.ConclusionThe 15q13.3 microdeletion syndrome is predominantly characterized by neuropsychiatric expression. There are implications for pre- and postnatal detection, genetic counseling, and anticipatory care.     

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith–Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett''s syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.     

Novel de novo SPOCK1 mutation in a proband with developmental delay,microcephaly and agenesis of corpus callosum

Whole exome sequencing made it possible to identify novel de novo mutations in genes that might be linked to human syndromes (genotype first analysis). We describe a female patient with a novel de novo SPOCK1 variant, which has not been previously been associated with a human phenotype. Her features include intellectual disability with dyspraxia, dysarthria, partial agenesis of corpus callosum, prenatal-onset microcephaly and atrial septal defect with aberrant subclavian artery. Previous genetic, cytogenomic and metabolic studies were unrevealing. At age 13 years, exome sequencing on the patient and her parents revealed a de novo novel missense mutation in SPOCK1 (coding for Testican-1) on chromosome 5q31: c.239A>T (p.D80V). This mutation affects a highly evolutionarily conserved area of the gene, replacing a polar aspartic acid with hydrophobic nonpolar valine, and changing the chemical properties of the protein product, likely representing a pathogenic variant. Previous microdeletions of 5q31 including SPOCK1 have suggested genes on 5q31 as candidates for intellectual disability. No mutations or variants in other genes potentially linked to her phenotype were identified. Testicans are proteoglycans belonging to the BM-40/SPARC/osteonectin family of extracellular calcium-binding proteins. Testican-1 is encoded by the SPOCK1 gene, and mouse models have been shown it to be strongly expressed in the brain and to be involved in neurogenesis. We hypothesize that because this gene function is critical for neurogenesis, mutations could potentially lead to a phenotype with developmental delay and microcephaly.     

A novel mosaic 1q32.1 microduplication identified through Chromosome Microarray Analysis: narrowing the smallest critical region including KDM5B gene found associated with neurodevelopmetal disorders

Microduplications involving 1q32.1 chromosomal region have been rarely reported in literature. Patients with these microduplications suffer from intellectual disability, developmental delay and a number of dysmorphic features, although no clear karyotype/phenotype correlation has yet been determined.In this case report we describe two monochorionic-diamniotic twins with intellectual disability, abnormality of coordination and dysmorphic features associated with a de novo 280 kb mosaic microduplication of 1q32.1 chromosomal region, identified using a Chromosome Microarray Analysis (CMA) and confirmed by quantitative PCR analysis.The duplicated region encompassed entirely three OMIM genes KDM5B (*605393), KLHL12 (*614522), RABIF (*603417) and involved partially SYT2 (*600104).This unique case report allows to redefine the critical 1q32.1 microduplicated region implicated in the ethiopathogenesis of intellectual disability and developmental delay. Furthermore, it suggests that KDM5B gene can have a pivotal role in the development of neurodevelopmental disorders through its demethylase activity.     

Neurodevelopmental features in 2q23.1 microdeletion syndrome: report of a new patient with intractable seizures and review of literature

2q23.1 microdeletion syndrome is a recently characterized chromosomal aberration disorder uncovered through array comparative genomic hybridization (array CGH). Although the cardinal feature is intellectual disability (ID), neurodevelopmental features of the syndrome have not been systematically reviewed. We present a 5-year-old boy with severe psychomotor developmental delay/ID, progressive microcephaly with brain atrophy, growth retardation, and several external anomalies. He manifested intractable epilepsy, effectively treated with combined antiepileptic drug therapy including topiramate. Array CGH demonstrated a de novo interstitial deletion of approximately 1?Mb at 2q23.1-q23.2, involving four genes including MBD5. Nineteen patients have been reported to have the syndrome, including present patient. All patients whose data were available had ID, 17 patients (89%) had seizures, and microcephaly was evident in 9 of 18 patients (50%). Deletion sizes ranged from 200?kb to 5.5?Mb, comprising 1-15 genes. MBD5, the only gene deleted in all patients, is considered to be responsible for ID and epilepsy. Furthermore, the deletion junction was sequenced for the first time in a patient with the syndrome; and homology of three nucleotides, identified at the distal and proximal breakpoints, suggested that the deletion might have been mediated by recently-delineated genomic rearrangement mechanism Fork Stalling and Template Switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR).     

2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features

We report a 2-year-old female who initially presented with seizures, developmental delay and dysmorphic features and was found to have a 0.3 Mb deletion at chromosome 2q23.1 encompassing the critical seizure gene, MBD5. Her distinct physical features include bifrontal narrowing with brachycephaly, low anterior hairline, hypotonic facial features with short upturned nose, flat nasal bridge, hypertelorism, tented upper lip with everted lower lip, downturned corners of her mouth, and relatively coarse facial features including thickened tongue. She also had a short neck, brachytelephalangy, clinodactyly, and hypertrichosis. At 3½ years she developed progressive ataxia and lost vocabulary at the age of 4. Regression has been reported in one other case of MBD5 deletion. MBD5 is a member of the methyl binding gene family and appears to be responsible for regulating DNA methylation in the central nervous system. Our patient was entirely deleted for the MBD5 gene with partial loss of the EPC2 gene, which suggests that haploinsufficiency of MBD5 is responsible for the distinct phenotype observed. This supports the hypothesis that MBD5 is indeed the critical gene implicated for the findings seen in patients with deletions of chromosome 2q23.1. Further studies are necessary to delineate the role that the MBD5 gene plays in the development of the brain and these specific physical characteristics.     

2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features

We report a 2-year-old female who initially presented with seizures, developmental delay and dysmorphic features and was found to have a 0.3 Mb deletion at chromosome 2q23.1 encompassing the critical seizure gene, MBD5. Her distinct physical features include bifrontal narrowing with brachycephaly, low anterior hairline, hypotonic facial features with short upturned nose, flat nasal bridge, hypertelorism, tented upper lip with everted lower lip, downturned corners of her mouth, and relatively coarse facial features including thickened tongue. She also had a short neck, brachytelephalangy, clinodactyly, and hypertrichosis. At 3½ years she developed progressive ataxia and lost vocabulary at the age of 4. Regression has been reported in one other case of MBD5 deletion. MBD5 is a member of the methyl binding gene family and appears to be responsible for regulating DNA methylation in the central nervous system. Our patient was entirely deleted for the MBD5 gene with partial loss of the EPC2 gene, which suggests that haploinsufficiency of MBD5 is responsible for the distinct phenotype observed. This supports the hypothesis that MBD5 is indeed the critical gene implicated for the findings seen in patients with deletions of chromosome 2q23.1. Further studies are necessary to delineate the role that the MBD5 gene plays in the development of the brain and these specific physical characteristics.     

Haploinsufficiency of CELF4 at 18q12.2 is associated with developmental and behavioral disorders, seizures, eye manifestations, and obesity

Only 20 patients with deletions of 18q12.2 have been reported in the literature and the associated phenotype includes borderline intellectual disability, behavioral problems, seizures, obesity, and eye manifestations. Here, we report a male patient with a de novo translocation involving chromosomes 12 and 18, with borderline IQ, developmental and behavioral disorders, myopia, obesity, and febrile seizures in childhood. We characterized the rearrangement with Affymetrix SNP 6.0 Array analysis and next-generation mate pair sequencing and found truncation of CELF4 at 18q12.2. This second report of a patient with a neurodevelopmental phenotype and a translocation involving CELF4 supports that CELF4 is responsible for the phenotype associated with deletion of 18q12.2. Our study illustrates the utility of high-resolution genome-wide techniques in identifying neurodevelopmental and neurobehavioral genes, and it adds to the growing evidence, including a transgenic mouse model, that CELF4 is important for human brain development.     

Autosomal insertional translocation mimicking an X-linked mode of inheritance

Unbalanced insertional translocations are a rare cause of intellectual disability. An unbalanced insertional translocation is a rare chromosomal imbalance, which may result from a balanced insertional translocation present in a phenotypically normal parent. We report here three brothers with intellectual disability, short stature, microcephaly, craniofacial anomalies and small testes. Since their parents and their sister were all phenotypically normal, the pattern of the family suggested an X-linked mode of inheritance. Surprisingly, we identified by array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) in the three brothers an 8q22.3q23.2 deletion resulting from a balanced insertional translocation present in their healthy father. The deletion encompassed the ZFPM2 gene known to be involved in gonadal development, which is consistent with the small testes and abnormal endocrine dosages in the affected brothers. The present report also illustrates that parental analyses by aCGH or qPCR methods are not sufficient when a de novo deletion or duplication is identified in an affected child and that FISH analysis should be performed on metaphase spreads in both parents to deliver an accurate genetic counseling.     

A non-synonymous coding change in the CYP19A1 gene Arg264Cys (rs700519) does not affect circulating estradiol, bone structure or fracture

Background

Rett syndrome (RTT) is a severe, progressive, neurodevelopmental disorder predominantly observed in females that leads to intellectual disability. Mutations and gross rearrangements in MECP2 account for a large proportion of cases with RTT. A limited number of twin pairs with RTT have also been reported in literature.

Case Presentation

We investigated 13 year old, monozygotic twin females with RTT and some noticeable differences in development using a combinatorial approach of sequencing and Taqman assay. Monozygosity status of the twins was confirmed by informative microsatellite markers.

Conclusions

The twins shared a de novo deletion in exon 3 in the MBD domain of MECP2. To the best of our knowledge, this is only the second report of genetic analysis of a monozygotic twin pair.     

SCAPER‐associated nonsyndromic autosomal recessive retinitis pigmentosa

Mutations in the gene SCAPER (S ‐phase C yclinA A ssociated P rotein residing in the E ndoplasmic R eticulum) have recently been identified as causing syndromic autosomal recessive retinitis pigmentosa with the extraocular manifestations of intellectual disability and attention‐deficit/hyperactivity disorder. We present the case of an 11‐year‐old boy that presented to our clinic with the complaint of decreased night vision. Clinical presentation, family history, and diagnostic imaging were congruent with the diagnosis of autosomal recessive retinitis pigmentosa. Genetic testing of the patient and both parents via whole‐exome sequencing revealed the homozygous mutation c.2023‐2A>G in SCAPER. Unique to our patient's presentation is the absence of intellectual disability and attention‐deficit/hyperactivity disorder, suggesting that SCAPER‐associated retinitis pigmentosa can also present without systemic manifestations.     

Retrospective identification of patients with SRRM2-related neurodevelopmental disorder in a single tertiary children's hospital

SRRM2-related neurodevelopmental disorder is a recently described genetic diagnosis caused by loss-of-function variants in SRRM2. In order to understand the clinical spectrum of SRRM2-related neurodevelopmental disorder, we performed a retrospective exome data and clinical chart review at a single tertiary children's hospital, Children's Hospital of Philadelphia (CHOP). Among approximately 3100 clinical exome sequencing cases performed at CHOP, we identified three patients with SRRM2 loss-of-function pathogenic variants, in addition to one patient previously described in the literature. Common clinical features include developmental delay, attention deficit hyperactivity disorder, macrocephaly, hypotonia, gastroesophageal reflux, overweight/obesity, and autism. While developmental disabilities are commonly seen in all individuals with SRRM2 variants, the degree of developmental delay and intellectual disability is variable. Our data suggest that SRRM2-related neurodevelopmental disorder can be identified in 0.3% of individuals with developmental disabilities receiving exome sequencing.