Gilbert-Dussardier Brigitte, Briand-Suleau Audrey, Laurendeau Ingrid, Bilan Frédéric, Cavé Hélène, Verloes Alain, Vidaud Michel, Vidaud Dominique, Pasmant Eric
Service de Génétique, C.H.U. de Poitiers, Centre de Référence Anomalies du Développement Ouest, Poitiers, France.
EA 3808 Université de Poitiers, Poitiers, France.
Orphanet J Rare Dis. 2016 Jul 22;11(1):101. doi: 10.1186/s13023-016-0479-y.
RAS/MAPK pathway germline mutations were described in Rasopathies, a class of rare genetic syndromes combining facial abnormalities, heart defects, short stature, skin and genital abnormalities, and mental retardation. The majority of the mutations identified in the Rasopathies are point mutations which increase RAS/MAPK pathway signaling. Duplications encompassing RAS/MAPK pathway genes (PTPN11, RAF1, MEK2, or SHOC2) were more rarely described. Here we report, a syndromic familial case of a 12p duplication encompassing the dosage sensitive gene KRAS, whose phenotype overlapped with rasopathies. The patient was referred because of a history of mild learning disabilities, small size, facial dysmorphy, and pigmentation abnormalities (café-au-lait and achromic spots, and axillar lentigines). This phenotype was reminiscent of rasopathies. No mutation was identified in the most common genes associated with Noonan, cardio-facio-cutaneous, Legius, and Costello syndromes, as well as neurofibromatosis type 1. The patient constitutional DNA exhibited a ~10.5 Mb duplication at 12p, including the KRAS gene. The index case's mother carried the same chromosome abnormality and also showed development delay with short stature, and numerous café-au-lait spots. Duplication of the KRAS gene may participate in the propositus phenotype, in particular of the specific pigmentation abnormalities. Array-CGH or some other assessment of gene/exon CNVs of RAS/MAPK pathway genes should be considered in the evaluation of individuals with rasopathies.
RAS/MAPK通路种系突变在Rasopathies中被描述，Rasopathies是一类罕见的遗传综合征，其特征包括面部异常、心脏缺陷、身材矮小、皮肤和生殖器异常以及智力迟钝。在Rasopathies中鉴定出的大多数突变是点突变，这些突变会增加RAS/MAPK通路信号传导。包含RAS/MAPK通路基因（PTPN11、RAF1、MEK2或SHOC2）的重复则较少被描述。在此，我们报告了一例综合征性家族病例，该病例为12号染色体短臂重复，包含剂量敏感基因KRAS，其表型与Rasopathies重叠。该患者因有轻度学习障碍、身材矮小、面部畸形和色素沉着异常（咖啡牛奶斑和色素脱失斑以及腋窝雀斑）的病史而前来就诊。这种表型让人联想到Rasopathies。在与努南综合征、心面皮肤综合征、勒吉乌斯综合征和科斯特洛综合征以及1型神经纤维瘤病相关的最常见基因中未发现突变。该患者的基因组DNA在12号染色体短臂上显示出约10.5 Mb的重复，包括KRAS基因。先证者的母亲携带相同的染色体异常，也表现出发育延迟、身材矮小以及大量咖啡牛奶斑。KRAS基因的重复可能参与了先证者的表型，特别是特定的色素沉着异常。在评估患有Rasopathies的个体时，应考虑采用阵列比较基因组杂交或对RAS/MAPK通路基因的基因/外显子拷贝数变异进行其他评估。
