Fieremans Nathalie, Van Esch Hilde, Holvoet Maureen, Van Goethem Gert, Devriendt Koenraad, Rosello Monica, Mayo Sonia, Martinez Francisco, Jhangiani Shalini, Muzny Donna M, Gibbs Richard A, Lupski James R, Vermeesch Joris R, Marynen Peter, Froyen Guy
Human Genome Laboratory, Department of Human Genetics, KU Leuven, Belgium.
Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium.
Hum Mutat. 2016 Aug;37(8):804-11. doi: 10.1002/humu.23012. Epub 2016 May 25.
Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole-exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.
智力障碍（ID）是一种异质性疾病，在许多情况下分子病因不明。以前，由于男性X染色体的半合子状态，X连锁智力障碍（XLID）研究主要集中在男性身上。携带突变基因的女性通常不受影响，因为她们有第二个正常等位基因，或者在大多数细胞中突变的X染色体发生失活（偏斜）。然而，对于女性ID患者，我们推测X染色体失活偏斜的存在可能是X染色体ID病因的一个指标。我们分析了288名女性ID患者的X染色体失活模式，发现22名（7.6%）有极端偏斜（>90%），这显著高于一般人群中的观察值（3.6%；P = 0.029）。对19名有极端偏斜的女性进行全外显子组测序，在XLID基因DDX3X、NHS、WDR45、MECP2和SMC1A中的6名女性中发现了致病变异。有趣的是，在其中3名患者中，逃避X染色体失活的基因变异可能同时导致XLID和X染色体失活偏斜。此外，在MED12、HDAC8和TAF9B中检测到可能仅导致偏斜的变异。所有测试的候选致病变异都是新发事件。因此，极端偏斜是女性患者中存在X连锁变异的一个良好指标。
