Defining the 3'Epigenetic Boundary of the Promoter and Its Loss in Individuals with Fragile X Syndrome.

This study characterizes the DNA methylation patterns specific to fragile X syndrome (FXS) with a full mutation (FM > 200 CGGs), premutation (PM 55-199 CGGs), and X inactivation in blood and brain tissues at the 3' boundary of the promoter. Blood was analyzed from 95 controls and 462 individuals (32% males) with FM and PM alleles. Brain tissues (62% males) were analyzed from 12 controls and 4 with FXS.

Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16 579 Newborns by Using a Novel Genomic Workflow.

Importance: Newborn screening for Angelman syndrome (AS), Prader-Willi syndrome (PWS), and chromosome 15 duplication syndrome (Dup15q) may lead to benefit from early diagnosis and treatment.

Objective: To examine the feasibility of newborn screening for these chromosome 15 imprinting disorders at population scale.

Design, Setting, And Participants: In this diagnostic study, the validation data set for the first-tier SNRPN test, called methylation-specific quantitative melt analysis (MS-QMA), included 109 PWS, 48 AS, 9 Dup15q, and 1190 population control newborn blood spots (NBS) and peripheral tissue samples from participants recruited from January 2000 to December 2016.

In search of the earliest images of symmelia in works of art.

Symmelia (alias sirenomelia, mermaid malformation) is one of the most distinctive malformations which, not surprisingly, has attracted the attention of many artists, writers and other observers of the human condition. Works of art depicting symmelia date back at least two millennia. Some are anatomically based while others are more fanciful creations intended to stir the imagination.

Common pathogenesis for sirenomelia, OEIS complex, limb-body wall defect, and other malformations of caudal structures.

Decades of clinical, pathological, and epidemiological study and the recent application of advanced microarray and gene sequencing technologies have led to an understanding of the causes and pathogenesis of most recognized patterns of malformation. Still, there remain a number of patterns of malformation whose pathogenesis has not been established. Six such patterns of malformation are sirenomelia, VACTERL association, OEIS complex, limb-body wall defect (LBWD), urorectal septum malformation (URSM) sequence, and MURCS association, all of which predominantly affect caudal structures.

Chromosome 14 deletions, rings, and epilepsy genes: A riddle wrapped in a mystery inside an enigma.

The ring 14 syndrome is a rare condition caused by the rearrangement of one chromosome 14 into a ring-like structure. The formation of the ring requires two breakpoints and loss of material from the short and long arms of the chromosome. Like many other chromosome syndromes, it is characterized by multiple congenital anomalies and developmental delays.

Syndromic Autism Revisited: Review of the Literature and Lessons Learned.

Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, stereotyped behaviors, restricted interests, and impaired social skills. The severity of the neurobehavioral phenotype is variable and historically has been distinguished based on the presence or absence of additional symptoms, termed syndromic and nonsyndromic or idiopathic autism, respectively. However, although the advancement in genetic molecular technologies has brought an increased understanding of the pathophysiology of autism, most of this success has been in the diagnosis of syndromic disease, whereas the etiology of nonsyndromic autism remains less understood.

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation.

Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease.

Neurofibromatosis type 2 in Phelan-McDermid syndrome: Institutional experience and review of the literature.

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by rearrangements on chromosome 22q13.3 or sequence variants in SHANK3. Individuals with PMS caused by a 22q terminal deletion and a ring chromosome are at increased risk for Neurofibromatosis type 2 (NF2).

Autistic Disorder: A 20 Year Chronicle.

The course of 187 individuals ages 3-21 years with Autistic Disorder was traced through a period of 20 years (enrollment: 1995-1998, follow up: 2014-2019). Specific genetic and environmental causes were identified in only a minority. Intellectual disability coexisted in 84%.

Hydrocephaly associated with compound heterozygous alterations in TRAPPC12.

Background: Hydrocephalus is characterized by increased cerebrospinal fluid within the brain, a causally heterogeneous disorder estimated to affect 1 per 1,000 live births, with the most severe cases often leading to fetal demise. The large number of known genetic and environmental factors that contribute to hydrocephalus makes the differential diagnosis challenging.

Cases: Three consecutive pregnancies of an unrelated couple were found by ultrasound to carry fetuses with hydrocephaly.

Rare missense variant p.Ala505Ser in the ZAK protein observed in a patient with split-hand/foot malformation from a non-consanguineous pedigree.

Objective: Split-hand/foot malformation (SHFM) is a rare, often debilitating, congenital limb malformation. A single nucleotide polymorphism within the leucine zipper containing kinase AZK () gene was recently associated with SHFM in two consanguineous Pakistani pedigrees. We hypothesized that additional unrelated patients with the phenotype may carry a pathogenic mutation in .

X-linked intellectual disability: Phenotypic expression in carrier females.

To better understand the landscape of female phenotypic expression in X-linked intellectual disability (XLID), we surveyed the literature for female carriers of XLID gene alterations (n = 1098) and combined this with experience evaluating XLID kindreds at the Greenwood Genetic Center (n = 341) and at the University of Adelaide (n = 157). One-hundred forty-four XLID genes were grouped into nine categories based on the level of female phenotypic expression, ranging from no expression to female only expression. For each gene, the clinical presentation, gene expression in blood, X-inactivation (XI) pattern, biological pathway involved, and whether the gene escapes XI were noted.

Co-expression of long non-coding RNAs and autism risk genes in the developing human brain.

Background: Autism Spectrum Disorder (ASD) is the umbrella term for a group of neurodevelopmental disorders convergent on behavioral phenotypes. While many genes have been implicated in the disorder, the predominant focus of previous research has been on protein coding genes. This leaves a vast number of long non-coding RNAs (lncRNAs) not characterized for their role in the disorder although lncRNAs have been shown to play important roles in development and are highly represented in the brain.

Neurodevelopmental disorder-associated ZBTB20 gene variants affect dendritic and synaptic structure.

Dendritic spine morphology and dendritic arborization are key determinants of neuronal connectivity and play critical roles in learning, memory and behavior function. Recently, defects of ZBTB20, a BTB and zinc finger domain containing transcriptional repressor, have been implicated in a wide range of neurodevelopmental disorders, including intellectual disability and autism. Here we show distinct effects of expression of two major isoforms, long and short, of ZBTB20, and its neurodevelopmental disorder-linked variants, on dendritic architecture of cultured rat cortical pyramidal neurons.

A Rare De Novo Gene Mutation Affecting BDNF-Enhancer-Driven Transcription Activity Associated with Autism and Atypical Smith-Magenis Syndrome Presentation.

Deletions and mutations involving the Retinoic Acid Induced 1 () gene at 17p11.2 cause Smith-Magenis syndrome (SMS). Here we report a patient with autism as the main clinical presentation, with some SMS-like features and a rare de novo gene mutation, c.

X-linked intellectual disability update 2017.

The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing.

Integrative genomic analyses for identification and prioritization of long non-coding RNAs associated with autism.

Genetic studies have identified many risk loci for autism spectrum disorder (ASD) although causal factors in the majority of cases are still unknown. Currently, known ASD risk genes are all protein-coding genes; however, the vast majority of transcripts in humans are non-coding RNAs (ncRNAs) which do not encode proteins. Recently, long non-coding RNAs (lncRNAs) were shown to be highly expressed in the human brain and crucial for normal brain development.

Rai1 Haploinsufficiency Is Associated with Social Abnormalities in Mice.

Autism is characterized by difficulties in social interaction, communication, and repetitive behaviors; with different degrees of severity in each of the core areas. Haploinsufficiency and point mutations of are associated with Smith-Magenis syndrome (SMS), a genetic condition that scores within the autism spectrum range for social responsiveness and communication, and is characterized by neurobehavioral abnormalities, intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. To investigate the relationship between and social impairment, we evaluated the mice with a battery of tests to address social behavior in mice.

Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome.

Background: Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene . The mechanisms involved in the ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to the regulation of histone H3 and DNA methylation, while mutations in the gene may lead to the downstream epigenetic and transcriptional effects.

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.

Clinical Validation of Fragile X Syndrome Screening by DNA Methylation Array.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. It is most frequently caused by an abnormal expansion of the CGG trinucleotide repeat (>200 repeats) located in the promoter of the fragile X mental retardation gene (FMR1), resulting in promoter DNA hypermethylation and gene silencing. Current clinical tests for FXS are technically challenging and labor intensive, and may involve use of hazardous chemicals or radioisotopes.

DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome.

Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean.

Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.

The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development.

Recurrent duplications of 17q12 associated with variable phenotypes.

The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi-institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe.