Koochek M, Harvard C, Hildebrand M J, Van Allen M, Wingert H, Mickelson E, Holden J J A, Rajcan-Separovic E, Lewis M E S
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Clin Genet. 2006 Feb;69(2):124-34. doi: 10.1111/j.1399-0004.2005.00560.x.
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic aetiology. In approximately 1% of cases, duplication of the 15q11-13 region has been reported. We report the clinical, array-comparative genomic hybridization (CGH) and cytogenetic evaluation of two individuals from a multiplex family demonstrating autism due to a maternally inherited gain of 15q11-13. Our findings indicate that unlike most 15q11-13 gains, which are caused by interstitial duplication of this region or supernumerary marker chromosomes deriving from proximal 15q, the 15q gain in this family is the result of abnormal segregation of a cryptic familial translocation with breakpoints at 14q11.2 and 15q13.3. The affected members of this family were found to have a normal karyotype at >550 band resolution. This translocation was identified using the 1-Mb resolution whole genome array (Spectral Genomics). The affected individuals have a gain of seven clones from proximal 15q, a loss of two clones from proximal 14q and a gain of two clones from 6q. Fluorescent in situ hybridization (FISH) analysis with clones from chromosomes 14 and 15, combined with DAPI reverse banding, showed an abnormal karyotype with one normal chromosome 15 and the der(15) t(14;15)(q11.2.;q13.3), resulting in the gain of proximal 15q and the loss of proximal 14q in affected individuals. The duplication of two clones from 6q in the affected subjects was also found in unaffected members of the family. Our findings suggest that the gain of 15q in autism may in some cases be due to cryptic translocations with breakpoints in the pericentromic regions of chromosome 15 and a different acrocentric chromosome. Variation in the size of pericentromic regions of any acrocentric chromosome may justify karyotype and FISH studies of autistic probands and their parents using probes from the 15q proximal region to determine recurrence risk for autism in some families.
自闭症谱系障碍（ASD）是一组具有强烈遗传病因的神经发育障碍。据报道，约1%的病例存在15q11 - 13区域的重复。我们报告了一个来自多重家庭的两名个体的临床、阵列比较基因组杂交（CGH）和细胞遗传学评估，这两名个体因母系遗传的15q11 - 13区域增加而患有自闭症。我们的研究结果表明，与大多数由该区域的间质性重复或源自近端15q的额外标记染色体引起的15q11 - 13增加不同，该家族中的15q增加是一个隐匿性家族易位异常分离的结果，断点位于14q11.2和15q13.3。在>550条带分辨率下，该家族的受影响成员核型正常。使用1兆碱基分辨率的全基因组阵列（Spectral Genomics）鉴定出了这种易位。受影响个体从近端15q获得了7个克隆，从近端14q丢失了2个克隆，并从6q获得了2个克隆。用来自14号和15号染色体的克隆进行荧光原位杂交（FISH）分析，并结合DAPI反带，显示出异常核型，有一条正常的15号染色体和der(15) t(14;15)(q11.2.;q13.3)，导致受影响个体近端15q增加而近端14q丢失。在该家族的未受影响成员中也发现了受影响个体中来自6q的两个克隆的重复。我们的研究结果表明，自闭症中15q的增加在某些情况下可能是由于隐匿性易位，断点位于15号染色体和另一条不同的近端着丝粒染色体的着丝粒周围区域。任何近端着丝粒染色体着丝粒周围区域大小的变化可能说明，对于自闭症先证者及其父母，使用来自15q近端区域的探针进行核型和FISH研究，以确定某些家族中自闭症的复发风险是合理的。
