Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.

BACKGROUND: Individuals affected with autism often suffer additional co-morbidities such as intellectual disability. The genes contributing to autism cluster on a relatively limited number of cellular pathways, including chromatin remodeling. However, limited information is available on how mutations in single genes can result in such pleiotropic clinical features in affected individuals. In this review, we summarize available information on one of the most frequently mutated genes in syndromic autism the Activity-Dependent Neuroprotective Protein (ADNP). RESULTS: Heterozygous and predicted loss-of-function ADNP mutations in individuals inevitably result in the clinical presentation with the Helsmoortel-Van der Aa syndrome, a frequent form of syndromic autism. ADNP, a zinc finger DNA-binding protein has a role in chromatin remodeling: The protein is associated with the pericentromeric protein HP1, the SWI/SNF core complex protein BRG1, and other members of this chromatin remodeling complex and, in murine stem cells, with the chromodomain helicase CHD4 in a ChAHP complex. ADNP has recently been shown to possess R-loop processing activity. In addition, many additional functions, for instance, in association with cytoskeletal proteins have been linked to ADNP. CONCLUSIONS: We here present an integrated evaluation of all current aspects of gene function and evaluate how abnormalities in chromatin remodeling might relate to the pleiotropic clinical presentation in individual"s" with Helsmoortel-Van der Aa syndrome.

Protein interaction network analysis reveals genetic enrichment of immune system genes in frontotemporal dementia.

Interactors of protein products of known genes for frontotemporal dementia (FTD) are likely to be involved in the molecular pathways towards disease. We therefore applied protein interaction network (PIN) analysis to prioritize candidate genes for rare variant association analysis. We created an FTD-PIN starting from known FTD genes downloading their physical interactors and performed functional enrichment analyses. We identified overrepresented processes in FTD and selected genes (n = 440) belonging to these processes for rare variant analysis in a Belgian cohort of 228 FTD patients and 345 controls. SKAT-O analysis suggested TNFAIP3 as the top gene (p = 0.7 × 10-3) reaching near test-wide significance (p = 2.5 × 10-4). We then analyzed the TNFAIP3-subnetwork within the FTD-PIN which indicated enrichment of several immune signaling networks, suggesting that disrupted immune signaling may be implicated in TNFAIP3-related FTD. Our study demonstrates that integration of PINs with genetic data is a useful approach to increase the power for rare variant association analysis. Furthermore, we present a computational pipeline for identifying potential novel therapeutic targets and risk-modifying variants.

Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease.

Expanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease.

A Survey of Rare Epigenetic Variation in 23,116 Human Genomes Identifies Disease-Relevant Epivariations and CGG Expansions.

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ∼1 in 3,000 and ∼1 in 6,000, respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of variation data and monozygous twin pairs suggests that approximately two-thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one-third are likely sporadic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, validated the presence of CGG expansions at several loci, and identified the putative molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many hypermethylated CGG repeat expansions.

Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

Whole genome sequencing of a dizygotic twin suggests a role for the serotonin receptor HTR7 in autism spectrum disorder.

Whole genome sequencing of a severely affected dizygotic twin with an autism spectrum disorder and intellectual disability revealed a compound heterozygous mutation in the HTR7 gene as the only variation not detected in control databases. Each parent carries one allele of the mutation, which is not present in an unaffected stepsister. The HTR7 gene encodes the 5-HT7 serotonin receptor that is involved in brain development, synaptic transmission, and plasticity. The paternally inherited p.W60C variant is situated at an evolutionary conserved nucleotide and predicted damaging by Polyphen2. A mutation akin to the maternally inherited pV286I mutation has been reported to significantly affect the binding characteristics of the receptor. Therefore, the observed sequence alterations provide a first suggestive link between a genetic abnormality in the HTR7 gene and a neurodevelopmental disorder. © 2016 Wiley Periodicals, Inc.

Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: A case report suggesting a genotype-phenotype correlation.

VPS45 mutations cause severe congenital neutropenia (SCN). We report on a girl with SCN and neurological impairment harboring a homozygous p.E238K mutation in VPS45 (vacuolar sorting protein 45). She successfully underwent hematopoietic stem cell transplantation. Our findings delineate the phenotype and indicate a possible genotype-phenotype correlation for neurological involvement.

Five patients with a chromosome 1q21.1 triplication show macrocephaly, increased weight and facial similarities.

Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intrachromosomal recombination.

Balanced translocations in mental retardation.

Over the past few decades, the knowledge on genetic defects causing mental retardation has dramatically increased. In this review, we discuss the importance of balanced chromosomal translocations in the identification of genes responsible for mental retardation. We present a database-search guided overview of balanced translocations identified in patients with mental retardation. We divide those in four categories: (1) balanced translocations that helped to identify a causative gene within a contiguous gene syndrome, (2) balanced translocations that led to the identification of a mental retardation gene confirmed by independent methods, (3) balanced translocations disrupting candidate genes that have not been confirmed by independent methods and (4) balanced translocations not reported to disrupt protein coding sequences. It can safely be concluded that balanced translocations have been instrumental in the identification of multiple genes that are involved in mental retardation. In addition, many more candidate genes were identified with a suspected but (as yet?) unconfirmed role in mental retardation. Some balanced translocations do not disrupt a protein coding gene and it can be speculated that in the light of recent findings concerning ncRNA's and ultra-conserved regions, such findings are worth further investigation as these potentially may lead us to the discovery of novel disease mechanisms.

Beckwith-Wiedemann-like macroglossia and 18q23 haploinsufficiency.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth condition with tumor proclivity linked to a genetic imbalance of a complex imprinted region in 11p15.5. A female child with features fitting in with the BWS diagnostic framework and an apparent loss of imprinting (LOI) of the IGF2 gene in 11p15.5 was also reported to have a de novo chromosome 18q segmental deletion (Patient 1), thus pointing at the location of a possible trans-activating regulator element for maintenance of IGF2 imprinting and providing one of the few examples of locus heterogeneity of BWS. A second child with de novo 18q23 deletion and features of macroglossia, naevus flammeus, bilateral inguinal hernia and transient neonatal hypoglycemia, thus also fitting in with the BWS diagnostic framework, is here fully reported (Patient 2). In this child, an analysis of the BWS1 locus precluded any paternal isodisomy and showed a normal imprinting pattern (mono-allelic expression of IGF2 and normal H19 and CDKN1OT1/LIT1 methylation index). In Patients 1 and 2, deletions were shown to overlap, defining a minimal region of haplo-insufficiency of 3.8-5.6 Mb in 18q23. We conclude that this region provides a candidate location for an original macroglossia condition with strong overlap with BWS, but without obvious upstream functional relationship with the BWS1 locus in 11p15.5. Because this minimal region of haplo-insufficiency falls into a common region of deletion in 18q- syndrome, we inferred that this macroglossia condition would follow a recessive pattern of inheritance.

Fragile sites and human disease.

A relationship between fragile sites, specific genomic regions visible as gaps or breaks on cultivated chromosomes, and human disease has been proposed many years ago. Evidence for a role of the ubiquitously expressed common fragile sites characterized by peculiar genome architecture in cancer has been accumulated over the last years. In contrast, a relationship between the second main group of fragile sites characterized by repeat expansion, the rare fragile sites, and mental retardation has been proposed many years ago, but after the molecular cloning of FRAXA and FRAXE both unequivocally involved in mental retardation, no additional fragile sites linked with mental retardation have been cloned for over a decade. The recent cloning of new fragile sites and the identification of the associated genes allow us to readdress this old paradigm and to speculate on the role these might play in human disease.