American Journal of Medical Genetics 117A:65–71 (2003) Cryptic t(1;12)(q44;p13.3) Translocation in a Previously Described Syndrome With Polymicrogyria, Segregating as an Apparently X-Linked Trait

We report on the multistep progression to the correct genetic diagnosis in an appar-ently new syndrome of mental retardation and multiple congenital anomalies, includ-ing hypogenitalism and polymicrogyria. We had previously reported it as an X-linked condition affecting four members (three males and one female) of a family [Zollino et al., 1992: Am J Med Genet 43:452–457]. Two of the four patients, both males, presented with a brain abnormality that was initially described as pachygyria, while the remain-ing two (one male and one female) did not. Our present study includes a clinical follow-up on the patients, neuroradiological re-examination of one patient, X linkage studies and X inactivation analyses, and finally molecular cytogenetics, which allowed us to establish definitely the genetic causes of the condition. After the detection of a subtle t(1;12)(q44;p13.3) balanced translocation in healthy carriers, two unbalanced segrega-tion products were observed in different patients, resulting in 1q44qter monosomy and 12p13.3pter trisomy in patients with polymicrogyria and severe psychomotor delay, 12p13.3pter monosomy and 1q44qter trisomy in the other two patients without polymicrogyria, with less severe mental retardation and less distinctive physical anomalies. Thus, this condition is no longer to be considered X-linked, but the result of cryptic autosomal imbalance. Furthermore, this study identified an approximately 14 Mb interval in 1q44qter pathogenetically relat-ed to polymicrogyria. 2003 Wiley-Liss, Inc. KEY WORDS: cryptic chromosome imbal-ance in MR/MCA syndrome; 1q44qter and polymicrogy-ria; brain cortical dysplasia; neuronal migration disorde