elastin and Intellectual-Disability

Research into phenotype-genotype correlations in neurodevelopmental disorders has greatly elucidated the contribution of genetic and neurobiological factors to variations in typical and atypical development. Etiologically relatively homogeneous disorders, such as Williams syndrome (WS), provide unique opportunities for elucidating gene-brain-behavior relationships. WS is a neurogenetic disorder caused by a hemizygous deletion of approximately 25 genes on chromosome 7q11.23. This results in a cascade of physical, cognitive-behavioral, affective, and neurobiological aberrations. WS is associated with a markedly uneven neurocognitive profile, and the mature state cognitive profile of WS is relatively well developed. Although anecdotally, individuals with WS have been frequently described as unusually friendly and sociable, personality remains a considerably less well studied area. This paper investigates genetic influences, cognitive-behavioral characteristics, aberrations in brain structure and function, and environmental and biological variables that influence the social outcomes of individuals with WS. We bring together a series of findings across multiple levels of scientific enquiry to examine the social phenotype in WS, reflecting the journey from gene to the brain to behavior. Understanding the complex multilevel scientific perspective in WS has implications for understanding typical social development by identifying important developmental events and markers, as well as helping to define the boundaries of psychopathology.

Topics: Adolescent; Adult; Brain; Child; Child, Preschool; Chromosome Deletion; Chromosome Mapping; Chromosomes, Human, Pair 7; Cognition Disorders; Cross-Cultural Comparison; Elastin; Emotions; Female; Genotype; Humans; Infant; Intellectual Disability; Magnetic Resonance Imaging; Male; Personal Construct Theory; Personality Development; Phenotype; Social Environment; Williams Syndrome

Williams-Beuren syndrome (WBS) is a neurodevelopmental microdeletion disorder that usually occurs sporadically due to its location within a highly repetitive genomic region that is unstable and prone to unequal cross-over during meiosis. The consequential loss of chromosomal material includes approximately 1.5 Mb of DNA at 7q11.23. Whilst cases of dominant inheritance have been described in the literature, there have been few reports of molecular confirmation and none have carried out detailed genotyping. We describe a Bulgarian father and son with WBS detected by fluorescent in situ hybridisation (with an elastin gene probe) and loss of heterozygosity mapping using microsatellite markers located in the critical region. These individuals appear to have a common WBS heterozygous deletion, confirming the expected dominant transmission and adding to the few familial cases reported. The deletion includes the gene FKBP6 which has recently been shown to play a role in homologous chromosome pairing in meiosis and male fertility in mouse models. Homozygous Fkbp6 -/- male mice are infertile and our data suggests that haploinsufficiency for FKBP6 does not appear to preclude male fertility in WBS, although male infertility involving this gene has the potential to follow the mouse model as a human autosomal recessive condition.

Topics: Adult; Aortic Stenosis, Supravalvular; Chromosomes, Human, Pair 7; Elastin; Facies; Fathers; Gene Deletion; Gene Dosage; Genes, Dominant; Genotype; Haplotypes; Humans; Intellectual Disability; Loss of Heterozygosity; Male; Nuclear Family; Tacrolimus Binding Proteins; Williams Syndrome

Topics: Abnormalities, Multiple; Calcium-Binding Proteins; Child; Child, Preschool; Cleft Palate; Contractile Proteins; Cutis Laxa; Elastin; Extracellular Matrix Proteins; Face; Family Health; Fatal Outcome; Female; Genetic Linkage; Haplotypes; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Microsatellite Repeats; Pedigree; Protein-Lysine 6-Oxidase; Skin; Syndrome

Topics: Abnormalities, Multiple; DNA; DNA Mutational Analysis; Elastin; Growth Disorders; Humans; Intellectual Disability; Polymorphism, Single-Stranded Conformational; Syndrome

Topics: Adolescent; Brain; Cardiovascular Diseases; Cerebellum; Cerebral Cortex; Chromosomes, Human, Pair 7; Cognition; Down Syndrome; Elastin; Gene Deletion; Humans; Intellectual Disability; Intelligence; Language; Magnetic Resonance Imaging; Music; Williams Syndrome

Clinical and pathological observations of a 6-month-old-boy with Costello syndrome are reported. The main clinical findings were loose skin of the neck, hands, and feet, deep palmar and plantar creases, typical "coarse" face with thick lips and macroglossia, relative macrocephaly, mental retardation, short stature, arrhythmia, large size for gestational age, and poor feeding. At age 6 months he died of rhabdomyolysis. The major pathological findings were fine, disrupted, and loosely-constructed elastic fibers in the skin, tongue, pharynx, larynx, and upper esophagus, but not in the bronchi, alveoli, aorta, or coronary arteries. Hyperplasia of collagen fibers in the skin, hyperplasia of the mucous glands in the bronchus, narrowing of the pulmonary artery, degeneration of the atrial conduction system, calcification and ballooning of skeletal muscle fibers with infiltration of macrophages, and myoglobin depositions in the collecting ducts in the kidney were also observed. The degeneration of elastic fibers was confirmed in the skin of a second Costello syndrome patient. Expression of elastin mRNA in the patient's fibroblasts was normal in size and amount. Given that elastic fiber degeneration was observed in the tissues with clinical symptoms, we speculate that a defect of elastic fibers, possibly relating to alternative splicing in the elastin gene or to defects in elastin microfibrils, might be involved in the pathogenesis of Costello syndrome.

Topics: Abnormalities, Multiple; Adult; Child, Preschool; Developmental Disabilities; Elastic Tissue; Elastin; Female; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Pregnancy; RNA, Messenger; Syndrome

To investigate the frequency of deletions of the elastin gene in patients with Williams syndrome (WS), we screened 44 patients by both FISH and PCR amplification of a dinucleotide repeat polymorphism. FISH was performed using cosmids containing either the 5' or the 3' end of the elastin gene. PCR analysis was performed on the patients and their parents with a (CA)n repeat polymorphism found in intron 17 of the elastin locus. Of the 44 patients screened, 91% were shown to be deleted by FISH. Using the DNA polymorphism, both maternally (39%) and paternally (61%) derived deletions were found. Four patients were not deleted for elastin but have clinical features of WS. Since deletions of elastin cannot account for several features found in WS, these patients will be valuable in further delineation of the critical region responsible for the WS phenotype. Although PCR can be useful for determining the parental origin of the deletion, our results demonstrate that FISH analysis of the elastin locus provides a more rapid and informative test to confirm a clinical diagnosis of WS. The presence of two copies of the elastin locus in a patient does not, however, rule out WS as a diagnosis.

Topics: Abnormalities, Multiple; Aortic Valve Stenosis; Chromosomes, Human, Pair 7; Elastin; Face; Female; Gene Deletion; Growth Disorders; Humans; In Situ Hybridization, Fluorescence; Intellectual Disability; Karyotyping; Male; Polymerase Chain Reaction

Williams syndrome (WS) is a developmental disorder affecting connective tissue and the central nervous system. A common feature of WS, supravalvular aortic stenosis, is also a distinct autosomal dominant disorder caused by mutations in the elastin gene. In this study, we identified hemizygosity at the elastin locus using genetic analyses in four familial and five sporadic cases of WS. Fluorescent in situ hybridization and quantitative Southern analyses confirmed these findings, demonstrating inherited and de novo deletions of the elastin gene. These data indicate that deletions involving one elastin allele cause WS and implicate elastin hemizygosity in the pathogenesis of the disease.

Topics: Adult; Alleles; Aortic Valve Stenosis; Arteries; Blotting, Southern; Child; Child, Preschool; Chromosomes, Human, Pair 7; Connective Tissue Diseases; Developmental Disabilities; Elastin; Genes; Genotype; Humans; In Situ Hybridization, Fluorescence; Intellectual Disability; Pedigree; Sequence Deletion; Syndrome

A rare case of Williams syndrome diagnosed at the age of 41 is documented. The first subjective symptom was chest pain and the patient displayed many other features in addition to severe supravalvular aortic stenosis with a systolic gradient of 60 mmHg. The stenotic lesion had an area of 0.5 cm2, and was associated with dilated and tortuous coronary arteries. Extended aortoplasty was successfully performed and the postoperative course has been excellent without any cardiac symptoms. In spite of the severe cardiac lesions, this case had been largely asymptomatic and presented unusual features related to the diagnosis and management of this syndrome in an adult. The pattern of abnormalities found in this case suggested problems in relation to the calcitonin/calcitonin gene related peptide (CGRP) and the elastin gene occurring in embryonic organogenesis.

Topics: Abnormalities, Multiple; Adult; Aortic Valve Stenosis; Calcitonin Gene-Related Peptide; Elastin; Face; Female; Humans; Intellectual Disability; Syndrome; Time Factors

Topics: Collagen; Connective Tissue Diseases; Elastic Tissue; Elastin; Fragile X Syndrome; Humans; Intellectual Disability; Male; Sex Chromosome Aberrations; Skin