RESUMO
The proximal long arm of chromosome 15 has segmental duplications located at breakpoints BP1-BP5 that mediate the generation of NAHR-related microdeletions and microduplications. The classical Prader-Willi/Angelman syndrome deletion is flanked by either of the proximal BP1 or BP2 breakpoints and the distal BP3 breakpoint. The larger Type I deletions are flanked by BP1 and BP3 in both Prader-Willi and Angelman syndrome subjects. Those with this deletion are reported to have a more severe phenotype than individuals with either Type II deletions (BP2-BP3) or uniparental disomy 15. The BP1-BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes that are not imprinted. Reports of mutations or disturbed expression of these genes appear to impact behavioral and neurological function in affected individuals. Recently, reports of deletions and duplications flanked by BP1 and BP2 suggest an association with speech and motor delays, behavioral problems, seizures, and autism. We present a large cohort of subjects with copy number alteration of BP1 to BP2 with common phenotypic features. These include autism, developmental delay, motor and language delays, and behavioral problems, which were present in both cytogenetic groups. Parental studies demonstrated phenotypically normal carriers in several instances, and mildly affected carriers in others, complicating phenotypic association and/or causality. Possible explanations for these results include reduced penetrance, altered gene dosage on a particular genetic background, or a susceptibility region as reported for other areas of the genome implicated in autism and behavior disturbances.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Deficiências do Desenvolvimento/genética , Duplicação Gênica , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos Mentais/genética , Adolescente , Adulto , Síndrome de Angelman/genética , Transtorno Autístico/genética , Biomarcadores/metabolismo , Criança , Pré-Escolar , Transtornos Cromossômicos , Hibridização Genômica Comparativa , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Distúrbios da Fala/genética , Adulto JovemRESUMO
Intellectual disability affects approximately 2% of the population with males outnumbering females due to involvement of over 300 genes on the X chromosome. The most common form of X-linked intellectual disability (XLID) is fragile X syndrome. We report a family with an apparent XLID pattern with the proband, his mother and maternal half brother having an Xp21.3 deletion detected with chromosomal microarray analysis involving the interleukin 1 receptor accessory protein-like 1 (IL1RAPL1) gene. IL1RAPL1 is highly expressed in the postnatal brain, specifically hippocampus suggesting a specialized role in memory and learning abilities. The proband presented with intellectual disability, a broad face, prominent and wide nasal root, ptosis, a wide philtrum and a small mouth. XLID due to involvement of the IL1RAPL1 gene has been reported to cause nonsyndromic XLID. We report a new family with XLID due to partial deletion of IL1RAPL1, summarize reported literature and describe similar phenotypic similarities among the affected individuals in this family and those reported in the literature proposing that deletion of IL1RAPL1 may cause syndromic XLID. Additional reports are needed to further characterize whether syndromic features are related to disturbances of this gene.
Assuntos
Cromossomos Humanos X/genética , Deleção de Genes , Proteína Acessória do Receptor de Interleucina-1/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adolescente , Feminino , Testes Genéticos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Linhagem , FenótipoRESUMO
Autism spectrum disorders (ASDs) are neurobehavioral disorders characterized by abnormalities in three behavioral domains including social interaction, impaired communication, and repetitive stereotypic behaviors. ASD affects approximately 1% of children and is on the rise with significant genetic mechanisms underlying these disorders. We review the current understanding of the role of genetic and metabolic factors contributing to ASD with the use of new genetic technology. Fifty percent is diagnosed with chromosomal abnormalities, small DNA deletions/duplications, single-gene conditions, or metabolic disturbances. Genetic evaluation is discussed along with psychiatric treatment and approaches for selection of medication to treat associated challenging behaviors or comorbidities seen in ASD. We emphasize the importance of prioritizing treatment based on target symptom clusters and in what order for individuals with ASD, as the treatment may vary from patient to patient.
RESUMO
Obesity in humans is a complex polygenic trait with high inter-individual heritability estimated at 40-70%. Candidate gene, DNA linkage and genome-wide association studies (GWAS) have allowed for the identification of a large set of genes and genomic regions associated with obesity. Structural chromosome abnormalities usually result in congenital anomalies, growth retardation and developmental delay. Occasionally, they are associated with hyperphagia and obesity rather than growth delay. We report four new individuals with structural chromosome abnormalities involving 10q22.3-23.2, 16p11.2 and Xq27.1-q28 chromosomal regions with early childhood obesity and developmental delay. We also searched and summarized the literature for structural chromosome abnormalities reported in association with childhood obesity.