Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Clin Genet. 2022 Sep;102(3):182-190. doi: 10.1111/cge.14173. Epub 2022 Jun 14.
While inherited hemizygous variants in PHF6 cause X-linked recessive Borjeson-Forssman-Lehmann syndrome (BFLS) in males, de novo heterozygous variants in females are associated with an overlapping but distinct phenotype, including moderate to severe intellectual disability, characteristic facial dysmorphism, dental, finger and toe anomalies, and linear skin pigmentation. By personal communication with colleagues, we assembled 11 additional females with BFLS due to variants in PHF6. We confirm the distinct phenotype to include variable intellectual disability, recognizable facial dysmorphism and other anomalies. We observed skewed X-inactivation in blood and streaky skin pigmentation compatible with functional mosaicism. Variants occurred de novo in 10 individuals, of whom one was only mildly affected and transmitted it to her more severely affected daughter. The mutational spectrum comprises a two-exon deletion, five truncating, one splice-site and three missense variants, the latter all located in the PHD2 domain and predicted to severely destabilize the domain structure. This observation supports the hypothesis of more severe variants in females contributing to gender-specific phenotypes in addition to or in combination with effects of X-inactivation and functional mosaicism. Therefore, our findings further delineate the clinical and mutational spectrum of female BFLS and provide further insights into possible genotype-phenotype correlations between females and males.
虽然 PHF6 的遗传性半合子变异会导致男性 X 连锁隐性 Borjeson-Forssman-Lehmann 综合征（BFLS），但女性的新发杂合变异与重叠但不同的表型相关，包括中度至重度智力残疾、特征性面部畸形、牙齿、手指和脚趾异常以及线性皮肤色素沉着。通过与同事的个人交流，我们汇集了另外 11 名因 PHF6 变异而患有 BFLS 的女性。我们证实了独特的表型包括可变智力残疾、可识别的面部畸形和其他异常。我们观察到血液中存在偏性 X 失活和条纹状皮肤色素沉着，与功能嵌合体相容。变异是新发的，发生在 10 个人中，其中 1 人仅轻度受影响，并将其传递给她受影响更严重的女儿。突变谱包括两个外显子缺失、五个截断、一个剪接位点和三个错义变异，后者均位于 PHD2 结构域，预测严重破坏结构域结构。这一观察结果支持了这样一种假说，即女性中更严重的变异除了 X 失活和功能嵌合体的影响之外，或者与这些影响相结合，导致了性别特异性表型。因此，我们的发现进一步描绘了女性 BFLS 的临床和突变谱，并提供了进一步的证据支持女性和男性之间可能存在的基因型-表型相关性。
