UMR1163, Institut Imagine Unité, Université Paris Cité, Paris, France.
Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
Am J Med Genet A. 2024 Aug;194(8):e63591. doi: 10.1002/ajmg.a.63591. Epub 2024 Mar 27.
Incontinentia pigmenti (IP, Bloch-Sulzberger syndrome) is a multisystem disorder which associates specific skin lesions that evolves in four stages, and occasionally, central nervous system, eye, hair, and teeth involvement. Familial (35%) and sporadic (65%) cases are caused by pathogenic variants in the IKBKG gene. Here we report an unusual family, where, in two half-sisters affected by typical IP, molecular genetic analysis identified a likely pathogenic non-sense variant in the IKBKG gene of one of the sisters, the other being not a carrier. The strong clinical conviction motivated further molecular genetic investigations, which led to the characterization of a second variant in this unique family. X chromosome inactivation studies demonstrated the paternal origin of these two de novo variants. For genes with frequent de novo mutations, the coexistence of different pathogenic mutations in the same family is a possibility, and constitutes a challenge for genetic counseling.
遗传性皮肤病（IP，Bloch-Sulzberger 综合征）是一种多系统疾病，其特征为特定皮肤损伤，该损伤分为四个阶段，偶尔还会累及中枢神经系统、眼睛、头发和牙齿。35%的病例为家族性，65%的病例为散发性，由 IKBKG 基因突变引起。我们在此报告一个不常见的家族，其中两位半姐妹患有典型的 IP，分子遗传学分析确定了其中一位姐妹的 IKBKG 基因中存在一种可能的致病性无义变异，而另一位姐妹则不是携带者。强烈的临床诊断促使我们进行进一步的分子遗传学研究，从而在这个独特的家族中鉴定出第二种变异。X 染色体失活研究表明，这两种新生变异均来自父系。对于经常发生新生突变的基因，同一家庭中同时存在不同的致病性突变是一种可能，这对遗传咨询构成了挑战。
