Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia

Abstract

Schizophrenia is a severe, debilitating mental disorder characterized by profound disturbances of cognition, emotion and social functioning. The lifetime morbid risk is surprisingly uniform at slightly less than 1% across different populations and different cultures. The evidence of genetic risk factors is our strongest clue to the cause of schizophrenia. Linkage and association analyses have identified genes associated with the development of schizophrenia. However, most of the alleles or haplotypes identified thus far have only a weak association or are reported to be population specific. A deletion of 22q11.2 that causes the most common microdeletion syndrome (22q11DS) with an estimated prevalence of 1:2,500-1:4,000 live births may represent one of the greatest known genetic risk factors for schizophrenia. Schizophrenia is a late manifestation in approximately 30% of patients with 22q11.2 deletion, comparable to the risk to offspring of two parents with schizophrenia. Clinical and neuroimaging assessments indicate that 22q11DS-schizophrenia is a neurodevelopmental model of schizophrenia. Recent studies have provided evidence that haploinsufficiency of TBX1 is likely to be responsible for many of the physical features associated with the deletion. Most of the genes in the 22q11 deletion region are conserved together on mouse chromosome 16, enabling the generation of mouse models. Similarities in the cardiovascular and other phenotypes between 22q11DS patients and mouse models can provide important insights into roles of genes in neurobehavioral phenotypes. Because more than one gene in the 22q11DS region is likely to contribute to the marked risk for schizophrenia, further extensive studies are necessary. Analyses of 22q11DS will help clarify the molecular pathogenesis of schizophrenia.

Identification of human haploinsufficient genes and their genomic proximity to segmental duplications

“…For example, mental retardation associated with the 22q11 deletion syndrome is due to the combined effects of the haploinsufficient genes PRODH 23 and TBX1. 24 Our study has found that many haploinsufficient phenotypes describe developmental disorders and mental retardation, consistent with our finding that haploinsufficient genes are enriched in regulatory and developmental gene functions. SDs appear to be important in primate evolution and in shaping human genetic variation.…”

Looking past the lump: genetic aspects of inguinal hernia in children

“…Velopharyngeal dysfunction, palatal abnormalities, thymic hypoplasia, and hypoparathyroidism with resultant hypocalcemia occur commonly. There is a well-recognized increased incidence of schizophrenia (6%-30%) and behavioral disturbances [79]. Facial dysmorphism can be subtle, with hooded eyelids and a square shape of the nose being common features.…”

Newborn screening programs: Should 22q11 deletion syndrome be added?

“…43 Two relatively small studies indicate that the lifetime prevalence of schizophrenia is 25-30% for people with 22q11DS. [43][44][45][46] Compared with 22q11DS patients, only individuals who have a monozygotic co-twin with schizophrenia or two parents with schizophrenia have greater risk of developing schizophrenia. 43 Although schizophrenia is usually considered as an adultonset disorder, psychiatric disorders in childhood also occur in those with 22q11DS.…”