Copy number variants and rasopathies: germline KRASduplication in a patient with syndrome including pigmentation abnormalities

Brigitte Gilbert-Dussardier,
Audrey Briand-Suleau,
Ingrid Laurendeau,
Frédéric Bilan,
Hélène Cavé,
Alain Verloes,
Michel Vidaud,
Dominique Vidaud and
Eric PasmantEmail author

Orphanet Journal of Rare Diseases201611:101

DOI: 10.1186/s13023-016-0479-y

Received: 3 March 2016

Accepted: 1 July 2016

Published: 22 July 2016

Abstract

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, orSHOC2) 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.