Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?

Abstract

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/MAPK pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, GE reflux and integument abnormalities. Analysis of EGF stimulated fibroblasts revealed that P-MEK1/2 was ~50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.

PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome

“…Review of additional cases included in the literature and public databases such as DECIPHER and ISCA Consortium (with full clinical data) allowed us to narrow this SRO to a 113.5 kb segment (chr19:3979568-4093035; hg19; NCBI build 37) and excluded EEF2 (Figure 2). Thus, 31/37 individuals shared this SRO and others overlapped it partially (case 4 in reference, 22 patient 6 in our series and DECIPHER case 271675; Figure 2). On the other hand, three cases did not share the SRO (patient 10 in our series and DECIPHER cases 259222, 255689), although they shared some clinical findings, such as ID, wide nasal bridge, narrow forehead or vesicoureteral reflux, with the SRO's patients.…”

“…Table 1 also analyzes the frequency of several phenotypic features, and compares with previously reported cases (reviewed in Table 2 and references [18][19][20][21][22] ). Among them, developmental delay (DD), abnormal head size, speech delay, intellectual disability (ID), feeding problems, hypotonia and other dysmorphic features were the most prevalent, present in most deletion cases.…”

“…This SRO is shared by 11 of 13 patients (excluding patient 6 partially and patient 10 totally, both of whom have normal head size) and by 13/14 patients in previously reported cases. [18][19][20][21][22] This segment of~150 kb includes one microRNA (SNORD37) and four RefSeq genes: PIAS4, ZBTB7A, MAP2K2 and partially EEF2. Review of additional cases included in the literature and public databases such as DECIPHER and ISCA Consortium (with full clinical data) allowed us to narrow this SRO to a 113.5 kb segment (chr19:3979568-4093035; hg19; NCBI build 37) and excluded EEF2 (Figure 2).…”

“…In fact, using this experimental approach, we and others recently described new microdeletion or microduplication syndromes. [14][15][16][17] Here we report 13 new patients with proximal 19p13.3 submicroscopic rearrangements (11 deletions and 2 duplications) and review patients from the literature (14 cases; 13 deletions and 1 duplication) [18][19][20][21][22] and public genomic databases such as DECIPHER and ISCA Consortium (10 cases; 6 deletions and 4 duplications) for a total of 37 cases. We describe the phenotypic findings and suggest that these patients represent a new microdeletion/duplication syndrome at 19p13.3, with a 113.5 Kb critical region harboring three genes: ZBTB7A, MAP2K2 and PIAS4, the latter being a candidate gene for abnormal head size.…”

Aortic dilation, genetic testing, and associated diagnoses

“…In this population some of the diagnoses included major aneuploidies that should be easily [6][7][8][18][19][20][21][22][23][24][25] In many cases, in spite of lacking further supporting clinical evidence of a direct link between AoD and the genes involved in the remaining patients with cytogenetic abnormalities, other potential candidate genes with relationships to cardiac morphogenesis or pathology were identified ( Table 3). [26][27][28][29][30][31][32][33][34][35] We also were able to identify other less common genetic conditions in this population.…”