Autism spectrum disorder (ASD) consists of a genetically heterogenous group of neurobehavioral disorders characterized by impairment in three behavioral domains including communication, social ...interaction, and stereotypic repetitive behaviors. ASD affects more than 1% of children in Western societies, with diagnoses on the rise due to improved recognition, screening, clinical assessment, and diagnostic testing. We reviewed the role of genetic and metabolic factors which contribute to the causation of ASD with the use of new genetic technology. Up to 40 percent of individuals with ASD are now diagnosed with genetic syndromes or have chromosomal abnormalities including small DNA deletions or duplications, single gene conditions, or gene variants and metabolic disturbances with mitochondrial dysfunction. Although the heritability estimate for ASD is between 70 and 90%, there is a lower molecular diagnostic yield than anticipated. A likely explanation may relate to multifactorial causation with etiological heterogeneity and hundreds of genes involved with a complex interplay between inheritance and environmental factors influenced by epigenetics and capabilities to identify causative genes and their variants for ASD. Behavioral and psychiatric correlates, diagnosis and genetic evaluation with testing are discussed along with psychiatric treatment approaches and pharmacogenetics for selection of medication to treat challenging behaviors or comorbidities commonly seen in ASD. We emphasize prioritizing treatment based on targeted symptoms for individuals with ASD, as treatment will vary from patient to patient based on diagnosis, comorbidities, causation, and symptom severity.
Mammals have two complete sets of chromosomes, one from each parent with equal autosomal gene expression. Less than one percentage of human genes are imprinted or show expression from only one parent ...without changing gene structure, usually by DNA methylation, but reversible in gametogenesis. Many imprinted genes affect fetal growth and development accounting for several human disorders reviewed in this report.
Disorders include Prader-Willi and Angelman syndromes, the first examples of imprinting errors in humans, chromosome 15q11.2-q13.3 duplication, Silver-Russell syndrome, Beckwith-Weidemann syndrome, GNAS gene-related inactivation disorders (e.g. Albright hereditary osteodystrophy), uniparental chromosome 14 disomy, chromosome 6q24-related transient neonatal diabetes mellitus, parent of origin effects in 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome and 15q11-q13 single gene imprinted disorders.
Periconceptional and intrauterine life can be influenced by environmental factors and nutrition impacting DNA methylation. This process not only alters development of the fetus, but pregnancy complications may result from large fetal size. Epigenetic processes control imprinted gene functions and regulation with susceptibility to diseases as described. A better understanding of these processes will impact on care and treatment of affected individuals.
Prader-Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental ...delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes (
) from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion.
and
genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The
gene encodes a protein associated with fragile X syndrome. The
gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside-Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions.
Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild ...dysmorphic features are less commonly seen. The 15q11.2 BP1-BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ≤75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1-BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity.
Genetics of Obesity in Humans: A Clinical Review Mahmoud, Ranim; Kimonis, Virginia; Butler, Merlin G
International journal of molecular sciences,
09/2022, Letnik:
23, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The ...development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader-Willi, fragile X, Bardet-Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (
), the leptin receptor (
), proopiomelanocortin (
), prohormone convertase 1 (
), the melanocortin 4 receptor (
), single-minded homolog 1 (
), brain-derived neurotrophic factor (
), and the neurotrophic tyrosine kinase receptor type 2 gene (
) have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings.
The 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome is an emerging disorder that encompasses four genes (
, and
). When disturbed, these four genes can lead to cognitive impairment, language ...and/or motor delay, psychiatric/behavioral problems (attention-deficit hyperactivity, autism, dyslexia, schizophrenia/paranoid psychosis), ataxia, seizures, poor coordination, congenital anomalies, and abnormal brain imaging. This microdeletion was reported as the most common cytogenetic finding when using ultra-high- resolution chromosomal microarrays in patients presenting for genetic services due to autism with or without additional clinical features. Additionally, those individuals with Prader-Willi or Angelman syndromes having the larger typical 15q11-q13 type I deletion which includes the 15q11.2 BP1-BP2 region containing the four genes, show higher clinical severity than those having the smaller 15q11-q13 deletion where these four genes are intact. Two of the four genes (i.e.,
and
) are expressed in the brain and encode magnesium transporters. Magnesium is required in over 300 enzyme systems that are critical for multiple cellular functions, energy expenditure, protein synthesis, DNA transcription, and muscle and nerve function. Low levels of magnesium are found in those with seizures, depression, and acute or chronic brain diseases. Anecdotally, parents have administered magnesium supplements to their children with the 15q11.2 BP1-BP2 microdeletion and have observed improvement in behavior and clinical presentation. These observations require more attention from the medical community and should include controlled studies to determine if magnesium supplements could be a treatment option for this microdeletion syndrome and also for a subset of individuals with Prader-Willi and Angelman syndromes.
Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder due to errors in genomic imprinting with loss of imprinted genes that are paternally expressed from the chromosome 15q11-q13 ...region. Approximately 70% of individuals with PWS have a de novo deletion of the paternally derived 15q11-q13 region in which there are two subtypes (i.e., larger Type I or smaller Type II), maternal disomy 15 (both 15s from the mother) in about 25% of cases, and the remaining subjects have either defects in the imprinting center controlling the activity of imprinted genes or due to other chromosome 15 rearrangements. PWS is characterized by a particular facial appearance, infantile hypotonia, a poor suck and feeding difficulties, hypogonadism and hypogenitalism in both sexes, short stature and small hands and feet due to growth hormone deficiency, mild learning and behavioral problems (e.g., skin picking, temper tantrums) and hyperphagia leading to early childhood obesity. Obesity is a significant health problem, if uncontrolled. PWS is considered the most common known genetic cause of morbid obesity in children. The chromosome 15q11-q13 region contains approximately 100 genes and transcripts in which about 10 are imprinted and paternally expressed. This region can be divided into four groups: 1) a proximal non-imprinted region; 2) a PWS paternal-only expressed region containing protein-coding and non-coding genes; 3) an Angelman syndrome region containing maternally expressed genes and 4) a distal non-imprinted region. This review summarizes the current understanding of the genetic causes, the natural history and clinical presentation of individuals with PWS.
Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid ...or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene-protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed.
Mammals inherit two complete sets of chromosomes, one from the father and one from the mother, and most autosomal genes are expressed from both maternal and paternal alleles. Imprinted genes show ...expression from only one member of the gene pair (allele) and their expression are determined by the parent during production of the gametes. Imprinted genes represent only a small subset of mammalian genes that are present but not imprinted in other vertebrates. Genomic imprints are erased in both germlines and reset accordingly; thus, reversible depending on the parent of origin and leads to differential expression in the course of development. Genomic imprinting has been studied in humans since the early 1980’s and accounts for several human disorders. The first report in humans occurred in Prader-Willi syndrome due to a paternal deletion of chromosome 15 or uniparental disomy 15 (both chromosome 15s from only one parent) and similar genetic disturbances were reported later in Angelman syndrome.
Prader-Willi syndrome (PWS) is a rare, complex, neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans and leads to a shortened life expectancy. This ...report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS.
The US Prader-Willi Syndrome Association (PWSA (USA)) syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA (USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox proportional hazards.
A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 ± 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype.
These findings highlight the heightened vulnerability to obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS.Genet Med advance online publication 17 November 2016.
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