Holinski-Feder E, Reyniers E, Uhrig S, Golla A, Wauters J, Kroisel P, Bossuyt P, Rost I, Jedele K, Zierler H, Schwab S, Wildenauer D, Speicher M R, Willems P J, Meitinger T, Kooy R F
Department of Medical Genetics, University of Munich, Munich.
Am J Hum Genet. 2000 Jan;66(1):16-25. doi: 10.1086/302703.
In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.
在寻找智力迟钝的遗传病因过程中，我们研究了一个五代家族，该家族第四代和第五代中有10名个体患有轻度至中度智力迟钝以及轻度、非特异性的畸形特征。这种疾病以一种外显率降低的常染色体显性方式遗传。该谱系不同寻常，原因在于：（1）其规模；（2）患病个体仅出现在最后两代，这提示了遗传早现现象。标准的临床和实验室筛查方案以及扩展的细胞遗传学分析，包括使用高分辨率核型分析和多重荧光原位杂交（M-FISH），均未能揭示智力迟钝的病因。因此，通过连锁分析，使用微卫星标记进行了全基因组扫描。该表型与16号染色体p13.3区域连锁，并且意外地发现患者存在16号染色体短臂末端部分的缺失，这与ATR-16综合征患者中观察到的缺失相似。随后的荧光原位杂交分析表明，患者除了16号染色体短臂缺失外，还遗传了3号染色体长臂末端的重复。对必然携带者的荧光原位杂交分析显示，在这个家族中，16号染色体短臂和3号染色体长臂末端之间的平衡易位发生了分离。该病例强化了隐匿性（细胞遗传学上不可见）亚端粒易位在智力迟钝中的作用，据其他人估计，这种易位在5%-10%的病例中起作用。
