ABSTRACT
The term "recurrent constellations of embryonic malformations" (RCEM) is used to describe a number of multiple malformation associations that affect three or more body structures. The causes of these disorders are currently unknown, and no diagnostic marker has been identified. Consequently, providing a definitive diagnosis in suspected individuals is challenging. In this study, genome-wide DNA methylation analysis was conducted on DNA samples obtained from the peripheral blood of 53 individuals with RCEM characterized by clinical features recognized as VACTERL and/or oculoauriculovertebral spectrum association. We identified a common DNA methylation episignature in 40 out of the 53 individuals. Subsequently, a sensitive and specific binary classifier was developed based on the DNA methylation episignature. This classifier can facilitate the use of RCEM episignature as a diagnostic biomarker in a clinical setting. The study also investigated the functional correlation of RCEM DNA methylation relative to other genetic disorders with known episignatures, highlighting the common genomic regulatory pathways involved in the pathophysiology of RCEM.
Subject(s)
DNA Methylation , Humans , Female , Male , Abnormalities, Multiple/genetics , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/diagnosisABSTRACT
De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.
Subject(s)
Intellectual Disability , Neurodevelopmental Disorders , Humans , Animals , Facies , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/pathology , Phenotype , Drosophila , Intellectual Disability/pathology , Jumonji Domain-Containing Histone Demethylases/geneticsABSTRACT
Mosaic variants in the PIK3CA gene, encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), produce constitutive PI3K activation, which causes PIK3CA-related overgrowth spectrum disorders. To date, fewer than 20 patients have been described with germline alterations in PIK3CA. In this study, we describe three unrelated individuals with overgrowth and germline PIK3CA variants. These variants were discovered through whole-exome sequencing and confirmed as germline by testing multiple tissue types, when available. Functional analysis using Patient 1's fibroblast cell line and two previously reported patients' cell lines showed increased phosphorylation of AKT during cellular starvation revealing constitutive activation of the phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway. Alternatively, stimulation of the cells by fetal bovine serum produced a reduced response, indicating an activated status of the PI3K complex reducing the pathway response to further external stimulation. Additional studies utilizing Biolog Phenotype Microarray technology indicated reduced energy production when cells were exposed to growth factors stimulating the PI3K/AKT/mTOR pathway, confirming the trend observed in the AKT phosphorylation test after stimulation. Furthermore, treatment with inhibitors of the PI3K/AKT/mTOR pathway rescued the normal energy response in the patients' cells. Collectively, these data demonstrate that disease-causing germline PIK3CA variants have a functional consequence, similar to mosaic variants in the PI3K/AKT/mTOR pathway.
Subject(s)
Class I Phosphatidylinositol 3-Kinases , Genetic Diseases, Inborn , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolism , Germ Cells/metabolism , Mutation , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/metabolism , Genetic Diseases, Inborn/physiopathology , Germ-Line Mutation , PhosphorylationABSTRACT
De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants.
Subject(s)
Autism Spectrum Disorder , Neurodevelopmental Disorders , Animals , Mice , DNA-Binding Proteins/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Neurodevelopmental Disorders/genetics , RNAABSTRACT
Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a â¼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
Subject(s)
Autism Spectrum Disorder/genetics , Haploinsufficiency/genetics , Histone Deacetylases/metabolism , Intellectual Disability/genetics , Repressor Proteins/genetics , Acetylation , Adolescent , Animals , Child , Child, Preschool , DNA Copy Number Variations/genetics , Female , Histones/chemistry , Histones/metabolism , Humans , Infant , Larva/genetics , Magnetic Resonance Imaging , Male , Middle Aged , Models, Molecular , Mutation , Repressor Proteins/deficiency , Repressor Proteins/metabolism , Syndrome , Young Adult , Zebrafish/genetics , Zebrafish Proteins/deficiency , Zebrafish Proteins/geneticsABSTRACT
PURPOSE: This study aims to assess the diagnostic utility and provide reporting recommendations for clinical DNA methylation episignature testing based on the cohort of patients tested through the EpiSign Clinical Testing Network. METHODS: The EpiSign assay utilized unsupervised clustering techniques and a support vector machine-based classification algorithm to compare each patient's genome-wide DNA methylation profile with the EpiSign Knowledge Database, yielding the result that was reported. An international working group, representing distinct EpiSign Clinical Testing Network health jurisdictions, collaborated to establish recommendations for interpretation and reporting of episignature testing. RESULTS: Among 2399 cases analyzed, 1667 cases underwent a comprehensive screen of validated episignatures, imprinting, and promoter regions, resulting in 18.7% (312/1667) positive reports. The remaining 732 referrals underwent targeted episignature analysis for assessment of sequence or copy-number variants (CNVs) of uncertain significance or for assessment of clinical diagnoses without confirmed molecular findings, and 32.4% (237/732) were positive. Cases with detailed clinical information were highlighted to describe various utility scenarios for episignature testing. CONCLUSION: Clinical DNA methylation testing including episignatures, imprinting, and promoter analysis provided by an integrated network of clinical laboratories enables test standardization and demonstrates significant diagnostic yield and clinical utility beyond DNA sequence analysis in rare diseases.
Subject(s)
DNA Methylation , Genetic Testing , Rare Diseases , Humans , DNA Methylation/genetics , Rare Diseases/genetics , Rare Diseases/diagnosis , Genetic Testing/standards , Genetic Testing/methods , Female , Promoter Regions, Genetic/genetics , Male , DNA Copy Number Variations/genetics , Child , Adult , Child, Preschool , Genomic Imprinting/geneticsABSTRACT
Duplication of all genes associated with X-linked intellectual disability (XLID) have been reported but the majority of the duplications include more than one XLID gene. It is exceptional for whole XLID gene duplications to cause the same phenotype as sequence variants or deletions of the same gene. Duplication of PLP1, the gene associated with Pelizaeus-Merzbacher syndrome, is the most notable duplication of this type. More commonly, duplication of XLID genes results in very different phenotypes than sequence alterations or deletions. Duplication of MECP2 is widely recognized as a duplication of this type, but a number of others exist. The phenotypes associated with gene duplications are often milder than those caused by deletions and sequence variants. Among some duplications that are clinically significant, marked skewing of X-inactivation in female carriers has been observed. This report describes the phenotypic consequences of duplication of 22 individual XLID genes, of which 10 are described for the first time.
Subject(s)
Intellectual Disability , Humans , Female , Intellectual Disability/genetics , Genes, X-Linked/genetics , Gene Duplication , X Chromosome Inactivation/genetics , MutationABSTRACT
Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.
Subject(s)
Genetics, Medical , Humans , History, 20th Century , History, 21st Century , Human GeneticsABSTRACT
Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.
Subject(s)
DNA Demethylation , Developmental Disabilities/genetics , Developmental Disabilities/pathology , Dioxygenases/deficiency , Adult , Amino Acid Sequence , Autistic Disorder/genetics , Autistic Disorder/pathology , Child , Child, Preschool , Dioxygenases/chemistry , Dioxygenases/genetics , Embryonic Development , Female , Gene Expression Regulation, Developmental , Growth Disorders/genetics , Growth Disorders/pathology , Humans , Infant , Male , Middle Aged , Movement Disorders/genetics , Movement Disorders/pathology , Pedigree , Protein Conformation , Sequence Homology , Young AdultABSTRACT
Genes that are involved in the transcription process, mitochondrial function, glycoprotein metabolism, and ubiquitination dominate the list of 21 new genes associated with X-linked intellectual disability since the last update in 2017. The new genes were identified by sequencing of candidate genes (2), the entire X-chromosome (2), the whole exome (15), or the whole genome (2). With these additions, 42 (21%) of the 199 named XLID syndromes and 27 (25%) of the 108 numbered nonsyndromic XLID families remain to be resolved at the molecular level. Although the pace of discovery of new XLID genes has slowed during the past 5 years, the density of genes on the X chromosome that cause intellectual disability still appears to be twice the density of intellectual disability genes on the autosomes.
Subject(s)
Genes, X-Linked , Intellectual Disability , Humans , Mutation , Genes, X-Linked/genetics , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Exome , PedigreeABSTRACT
PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
Subject(s)
Mental Retardation, X-Linked , Protein Serine-Threonine Kinases , Symporters , Brain/abnormalities , Catalytic Domain/genetics , Hemizygote , Humans , Loss of Function Mutation , Male , Maternal Inheritance/genetics , Mental Retardation, X-Linked/genetics , Mutation, Missense , Phosphorylation , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/genetics , Symporters/metabolismABSTRACT
Chromosomal aneuploidies, microduplications and microdeletions are the most common confirmed genetic causes of spina bifida. Microduplications of Xq27 containing the SOX3 gene have been reported in 11 cases, confirming the existence of an X-chromosomal locus for spina bifida. A three generation kindred reported here with a SOX3 duplication has been identified in one of 17 kindreds with recurrences in the 29 years of the South Carolina Neural Tube Defect Prevention Program. Other recurrences during this time period included siblings with an APAF1 mutation, siblings with a CASP9 mutation, siblings with a microdeletion of 13q, and two sets of siblings with Meckel syndrome who did not have genetic/genomic studies performed.
Subject(s)
Neural Tube Defects , Spinal Dysraphism , Encephalocele , Humans , Mutation , Neural Tube Defects/genetics , Recurrence , SOXB1 Transcription Factors/genetics , Spinal Dysraphism/geneticsABSTRACT
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. The figure of Atargatis as a mermaid on a first century BC coin is one of the earliest known images of symmelia. A nearly 2000-year-old Native American pottery figure representing an infant with symmelia is another.
Subject(s)
Ectromelia , Humans , InfantABSTRACT
PURPOSE: We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested. METHODS: We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings). RESULTS: Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis. CONCLUSION: This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.
Subject(s)
DNA Methylation , Epigenomics , Canada , Europe , Humans , SyndromeABSTRACT
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. On the basis of the overlap of the component malformations, the co-occurrence in individual fetuses, and the findings on fetal examination, a common pathogenesis is proposed for these patterns of malformation. The presence of a single artery in the umbilical cord provides a visible clue to the pathogenesis of all cases of sirenomelia and 30%-50% of cases of VACTERL association, OEIS complex, URSM sequence, and LBWD. The single artery is formed by a coalescence of arteries that supply the yolk sac, arises from the descending aorta high in the abdominal cavity, and redirects blood flow from the developing caudal structures of the embryo to the placenta. This phenomenon during embryogenesis is termed vitelline vascular steal.
Subject(s)
46, XX Disorders of Sex Development/diagnosis , Abnormalities, Multiple/diagnosis , Anal Canal/abnormalities , Congenital Abnormalities/diagnosis , Ectromelia/diagnosis , Esophagus/abnormalities , Heart Defects, Congenital/physiopathology , Kidney/abnormalities , Limb Deformities, Congenital/physiopathology , Mullerian Ducts/abnormalities , Spine/abnormalities , Trachea/abnormalities , 46, XX Disorders of Sex Development/physiopathology , Abnormalities, Multiple/physiopathology , Anal Canal/blood supply , Anal Canal/physiopathology , Anus, Imperforate/physiopathology , Aorta/pathology , Arteries/pathology , Congenital Abnormalities/physiopathology , Ectromelia/physiopathology , Embryo, Mammalian , Esophagus/blood supply , Esophagus/physiopathology , Extremities/blood supply , Extremities/embryology , Extremities/growth & development , Female , Fetus , Hernia, Umbilical/physiopathology , Humans , Kidney/blood supply , Kidney/physiopathology , Mullerian Ducts/blood supply , Mullerian Ducts/physiopathology , Pregnancy , Scoliosis/physiopathology , Spine/blood supply , Spine/physiopathology , Torso/blood supply , Torso/physiopathology , Trachea/blood supply , Trachea/physiopathology , Umbilical Cord/blood supply , Umbilical Cord/physiopathology , Urogenital Abnormalities/physiopathologyABSTRACT
INTRODUCTION: Whole-exome sequencing (WES) has identified de novo variants in chromatin remodelling genes in patients with neurodevelopmental disorders (NDD). We report on a novel genetic discovery in chromatin remodelling in patients with NDD who also have corpus callosum (CC) anomalies. OBJECTIVE: To discover novel genes linked to both CC anomalies and NDD. METHODS: Clinical WES was performed for evaluation of NDD, identifying five patients with de novo variants in SUPT16H, a subunit of the FACT (facilitates chromatin transcription) complex. The clinical phenotypes, genetic results and brain MRIs were obtained and systematically reviewed. In silico protein function predictions were assessed and allele frequencies in control populations were compared. RESULTS: We identified four patients with de novo missense variants in SUPT16H and one patient with a de novo deletion including SUPT16H. These variants were not reported in the updated Genome Aggregation Database. When assayable, all protein products were predicted to be damaging. Symptoms included intellectual disability, autistic features, minor dysmorphic features and seizures. Anomalies of the CC were seen in all three patients with available brain imaging. CONCLUSION: Our findings implicate the gene SUPT16H in a novel disorder characterised by neurodevelopmental deficits and CC anomalies.
Subject(s)
Agenesis of Corpus Callosum/genetics , Cell Cycle Proteins/genetics , Genetic Predisposition to Disease , Neurodevelopmental Disorders/genetics , Transcription Factors/genetics , Adolescent , Agenesis of Corpus Callosum/physiopathology , Brain/diagnostic imaging , Brain/metabolism , Brain/physiopathology , Child , Child, Preschool , Corpus Callosum/physiopathology , Exome/genetics , Female , Humans , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Male , Mutation, Missense/genetics , Neurodevelopmental Disorders/physiopathology , Seizures/genetics , Seizures/physiopathology , Exome SequencingABSTRACT
A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in FAM50A. Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in FAM50A. This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding of the associated molecular mechanisms, and further enhances our ability to diagnose patients with rare disorders.
Subject(s)
DNA Methylation , Mental Retardation, X-Linked/genetics , Adult , Case-Control Studies , Child , DNA-Binding Proteins/genetics , Epigenome , Humans , Male , Mental Retardation, X-Linked/etiology , Middle Aged , Models, Genetic , Neurodevelopmental Disorders/genetics , RNA-Binding Proteins/geneticsABSTRACT
The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergence during fetal cortical development between BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss-of-function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop-gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD.
Subject(s)
Autism Spectrum Disorder/genetics , Genetic Predisposition to Disease , Haploinsufficiency , Intellectual Disability/genetics , Neurodevelopmental Disorders/genetics , Transcription Factors, General/genetics , Alleles , Amino Acid Substitution , Autism Spectrum Disorder/diagnosis , Gene Expression , Genetic Association Studies , Genotype , Humans , Intellectual Disability/diagnosis , Neurodevelopmental Disorders/diagnosis , Sequence DeletionABSTRACT
Strumae ovarii are neoplasms composed of normal-appearing thyroid tissue that occur within the ovary and rarely spread to extraovarian sites. A unique case of struma ovarii with widespread dissemination detected 48 years after removal of a pelvic dermoid provided the opportunity to reexamine the molecular nature of this form of neoplasm. One tumor, from the heart, consisting of benign thyroid tissue was found to have whole-genome homozygosity. Another tumor from the right mandible composed of malignant-appearing thyroid tissue showed whole-genome homozygosity and a deletion of 7p, presumably the second hit that transformed it into a cancerous tumor. Specimens from 2 other cases of extraovarian struma confined to the abdomen and 8 of 9 cases of intraovarian struma showed genome-wide segmental homozygosity. These findings confirm errors in meiosis as the origin of struma ovarii. The histological and molecular findings further demonstrate that even when outside the ovary, strumae ovarii can behave nonaggressively until they receive a second hit, thereafter behaving like cancer.
Subject(s)
Carcinoma/genetics , Genome, Human , Meiosis , Ovarian Neoplasms/genetics , Struma Ovarii/genetics , Teratoma/genetics , Adult , Aged , Carcinoma/diagnosis , Female , Gene Deletion , Heart Neoplasms/genetics , Heart Neoplasms/secondary , Homozygote , Humans , Mandibular Neoplasms/genetics , Mandibular Neoplasms/secondary , Middle Aged , Neoplasm Recurrence, Local , Oligonucleotide Array Sequence Analysis , Ovarian Neoplasms/diagnosis , Sequence Analysis, RNA , Struma Ovarii/diagnosis , Teratoma/diagnosis , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathologyABSTRACT
OBJECTIVE: To examine the prevalence and types of neural tube defects and the types of anomalies co-occurring with neural tube defects in 6 years before fortification of cereal grain flour with folic acid (1992-1998) and 20 years after fortification (1999-2018) in South Carolina, a state with a historically high prevalence of these birth defects. STUDY DESIGN: The prevalence of neural tube defects was determined by active and passive surveillance methods in South Carolina since 1992. The types of neural tube defects and co-occurring malformations were determined by prenatal ultrasound and post-delivery examination. RESULTS: In the 6 prefortification years, 363 neural tube defects were identified among 279 163 live births and fetal deaths (1/769), 305 (84%) of which were isolated defects of the calvaria or spine. In the 20 fortification years, there were significant reductions in the prevalence and percentage of isolated defects: 938 neural tube defects were identified among 1 165 134 live births and fetal deaths (1/1242), 696 (74.2%) of which were isolated. The current prevalence of neural tube defects in South Carolina (0.56/1000 live births and fetal deaths) is comparable with that nationwide. CONCLUSIONS: The continued occurrence of neural tube defects, the majority of which are isolated, after folic acid fortification of cereal grain flours suggests that additional prevention measures are necessary to reduce further the prevalence of these serious defects of the brain and spine.