Psychiatric Features in Children with Genetic Syndromes: Toward Functional Phenotypes
Section snippets
Genetic testing
Significant advances have been made in methods and availability of genetic testing in the past decade, allowing for increased precision in establishing a diagnosis for many individuals. In fact, the long-honored chromosome analysis (or karyotype), once the mainstay of genetic testing, is now often replaced as a first-line test with molecular methods, including fluorescent in situ hybridization (FISH), comparative genomic hybridization (CGH) microarray, and gene sequencing. A good analogy for
Genetics, Etiology, and Epidemiology
Initially described by John Langdon Down in 1866, the condition known eponymously as Down syndrome (DS) was determined to be caused by trisomy of chromosome 21 in the 1950s. Whereas the vast majority of individuals (more than 95%) with trisomy 21 have an entire additional chromosome 21 secondary to nondisjunction during gametogenesis, a smaller percentage of individuals will have trisomy 21 related to a chromosome translocation. An even smaller percentage of affected individuals will have
Genetics, Etiology, and Epidemiology
Fragile X syndrome (FXS) is recognized as the most common inherited form of mental retardation, with an incidence of approximately 1 in 3000, including affected males and females. The premutation/intermediate length mutation carrier frequency is much higher, approximately 1% in females26 and 1 in 800 males.
FXS is one of several “triplet repeat” neurologic disorders caused by expansion of a disease-specific trinucleotide repeat within a disease-specific gene. In FXS this trinucleotide repeat,
Genetics, Etiology, and Epidemiology
Classic Rett syndrome has a prevalence of approximately 1 in 10,000 females,57 although emerging information regarding the range of phenotypes associated with MECP2 alterations in both males and females will expand the clinical impact of this gene over time. MECP2 is located at Xq28 and encodes the MeCP2 protein responsible for decreasing transcription, and thus expression, of other genes. Loss of this inhibition in the brain probably results in overexpression of normally tightly regulated
Genetics, Etiology, and Epidemiology
The genes within the proximal region of the long arm of chromosome 15 demonstrate tightly regulated, specific parent-of-origin expression. This differential expression is controlled by imprinting, by which methylation of the DNA causes the selective silencing of genes from either the paternal or the maternal homolog. The genes within this region are variably expressed, with some genes expressed only when inherited paternally and others only when inherited maternally.
Loss of the paternally
Genetics, Etiology, and Epidemiology
Within the 15q11-q13 region are genes with specific parent of origin expression; some genes are exclusively expressed from the paternal allele and others are expressed only from the maternal allele. When there is loss of the normal expression of maternal alleles, Angelman syndrome (AS) results.96 This loss of expression can result from several molecular mechanisms including a deletion within the maternal chromosome homolog (70%–75%), paternal UPD of chromosome 15 (2%–5%), and imprinting defects
Genetics, Etiology, and Epidemiology
The co-occurrence of idiopathic hypercalcemia and supravalvar aortic stenosis was initially described in the 1960s106, 107, 108 and the full syndrome was eponymously named after cardiologists Williams and Buren. WS is primarily a sporadic condition with an approximate incidence of 1 in 10,000. A common chromosome microdeletion of 1.5 Mb at 7q11.23 is responsible for the full phenotype109; absence of the ELN gene is associated with the cardiac and connective tissue features, and loss of the LIMK1
Genetics, Etiology, and Epidemiology
Encompassing a wide range of physical phenotypes, including several eponymous syndromes, this microdeletion is thought to be the most common contiguous gene deletion, with general population estimates ranging from 1 in 3800 to 1 in 6000.126 The deletion is found in much higher frequency within populations selected for cardinal physical features including cleft lip/palate/bifid uvula and conotruncal cardiac malformations.
The classic 3-Mb deletion includes 30 genes, several of which appear to
Genetics, Etiology, and Epidemiology
Smith-Magenis syndrome (SMS) has been recognized since the 1980s152, 153, 154 and is caused by a deletion of chromosome 17p11.2.155, 156 The phenotype changes significantly over the life span, and diagnosis is largely dependent on the presence of structural malformations or recognition of the behavioral phenotype.
The critical region for SMS is a 1-Mb region157, 158 within the classic deletion of approximately 4 Mb.159, 160 Several genes within this region have been implicated in the features of
Genetics, Etiology, and Epidemiology
By definition, Turner syndrome (TS) occurs only in females and has an incidence of approximately 1 in 3000 live-born infant girls. At the most basic level, TS results when there is a single functioning X chromosome as a result of loss of the second sex chromosome in its entirety or more specifically, portions of the short arm of either the second X chromosome or the Y. Half of affected individuals will have a 45,X karyotype; a wide range of other structural X-chromosome malformations and mosaic
Genetics, Etiology, Epidemiology, Physical Features, and Medical Issues
Lesch-Nyhan syndrome is an X-linked disorder of purine metabolism resulting from decreased activity of hypoxanthine-guanine phosphoribosyltransferase. This diagnosis is often suspected because of the specific physical and behavioral phenotype seen in childhood; choreoathetosis, seizures, dystonia, and dysarthria are also frequently present. The diagnosis is established by measuring plasma or urine uric acid levels, which are markedly elevated. Medical treatment is primarily symptomatic, and
Common inborn errors of metabolism
Several other inborn errors of metabolism are associated with marked behavioral or psychiatric manifestations. Not all of these diagnoses are established in infancy through newborn screening, and many may not be diagnosed until the behavioral phenotype is well established. Although in general these diagnoses are rare, consideration should be given to a metabolic evaluation in individuals with suggestive medical and psychological features.
Phenylketonuria (PKU), resulting from a deficiency of
Summary
The identification of specific genetic diagnoses, including genotype-specific variations, presents the unique opportunity to study genotype/phenotype connections in child psychiatry. Multiple investigators have spent the last 2 decades characterizing the psychopathologic features associated with specific diagnoses, and the latest research seeks to connect specific facets of behavioral functioning, such as social gaze processing in TS, with genetic variance. These advances have implications for
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Practice Parameter for the Assessment and Treatment of Psychiatric Disorders in Children and Adolescents With Intellectual Disability (Intellectual Developmental Disorder)
2020, Journal of the American Academy of Child and Adolescent PsychiatryCitation Excerpt :Certain genetic syndromes are associated with increased rates of psychiatric and behavioral disorders. Table 119 lists behavioral phenotypes and psychiatric features in certain genetic syndromes associated with ID/IDD. Clinical consensus and existing guidelines from the Social Security Act, the Individuals with Disabilities Education Improvement Act (IDEA) of 2004, and the American Academy of Pediatrics (AAP)20,21 consistently recommend standardized developmental screening and support a variety of validated, parent-report screening tools for the early identification of developmental delays.
Association between CANCA1C gene rs1034936 polymorphism and alcohol dependence in bipolar disorder
2020, Journal of Affective DisordersCitation Excerpt :BD has a strong genetic component, as evidenced by high disease concordance among monozygotic vs. dizygotic twins (Edvardsen et al., 2008; Van Der Schot et al., 2009). Heritability estimates for BD have typically been reported to be about 75% (Lescai et al., 2017; Siegel and Smith, 2011), while evidence for genetic heterogeneity between clinical subtypes of BD has also been reported (Charney et al., 2017). Genome-wide association studies (GWAS) have indicated an association between BD and single nucleotide polymorphisms (SNPs) in a variety of genes including monoaminergic neurotransmitter systems, GABAergic, voltage depended ion channel, regulation of neuroplasticity and structural proteins (Calabrò et al., 2016; Gurung and Prata, 2017; Stahl et al., 2019).
Negative subthreshold psychotic symptoms distinguish 22q11.2 deletion syndrome from other neurodevelopmental disorders: A two-site study
2017, Schizophrenia ResearchCitation Excerpt :Both syndromes have overlapping phenotypic manifestations, including cardiovascular anomalies, calcium dysregulation, cognitive deficits, and high rates of psychiatric comorbidities (Campbell et al., 2009). As a group, individuals with neurodevelopmental disabilities (e.g., 22q11DS, WS, fragile X, or Turner syndrome) have higher rates of neuropsychiatric, cognitive, and social–behavioral deficits including nonverbal learning disorder, visuospatial deficits, attention deficit/hyperactivity disorder (ADHD), anxiety disorders, and affective disorders, compared to typically developing (TD) individuals (Schneider et al., 2014; Siegel and Smith, 2011; Weisman et al., 2015; Zarchi et al., 2014). Additionally, individuals with 22q11.2DS have a 30-fold increased risk of developing psychosis compared to TD individuals and individuals with other neurodevelopmental disabilities (10-fold) (Schneider et al., 2014).
Parental perspectives on the quality of life of children with Down syndrome
2022, Frontiers in PsychiatryThe effect of the adapted soccer programme on motor learning and psychosocial behaviour in adolescents with Down syndrome
2022, Journal of Intellectual Disability ResearchDevelopment of Down Syndrome Research Over the Last Decades–What Healthcare and Education Professionals Need to Know
2021, Frontiers in Psychiatry
A version of this article was previously published in the Child and Adolescent Psychiatric Clinics of North America, 19:2.