P-17

Lujan-Fryns and Opitz-Kaveggia syndromes: MED12 molecular screening

Cathy Paulino^I,II,*; Isabel Marques^I,*; Raquel Chaves^II; Paula Jorge^I; Rosário Santos^I

^IUnidade de Genética Molecular, Centro Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto - EPE, Porto, Portugal; Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
^IIUniversity of Trás-os-Montes and Alto Douro (UTAD), Department of Genetics and Biotechnology (DGB), Laboratory of Cytogenomics and Animal Genomics (CAG), Vila Real
* Equal contributors paulinocathy@gmail.com; isabel.medeiros.marques@gmail.com

Lujan-Fryns   syndrome   (LFS   -   OMIM   #309520)   is characterized as a rare form of X-linked Intellectual Disability (XLID), affecting mostly males. Clinically, the patients can be recognized by the facial morphology in addition to the presentation of some of the following features: tall marfanoid stature,  macrocephaly,  long  hands  with  hyperextensible digits, mild general hypotonia and mild to moderate cognitive deficits with several behavioural problems. Opitz-Kaveggia syndrome (FGS - OMIM #305450) is also a rare form of XLID. Patients show a distinctive facial appearance, a tall and prominent forehead, short stature, small prominente ears with simplified helical pattern, frontal hair upsweep, hypotonia and constipation. They frequently present mental retardation with developmental delay and a distinctive behaviour, with hyperactive personality and excessive talkativeness. FGS is characterized by clinical variability and genetic heterogeneity. There has been a clear association between MED12 gene and LF and FG syndromes. While in LFS a single recurrent mutation c.3020A>G in exon 22 was reported, in FGS two frequent mutations, c.2873G>A and c.2881C>T both located in exon 21, were previously described. This gene encodes for the mediator of RNA polymerase II transcription subunit 12, an essential subunit of the mediator complex, interacting with different developmental pathways and involved in the regulation of neuronal gene expression.

Until recently, the molecular genetic analysis of MED12 in our laboratory consisted of sequence analysis of the coding exons and flanking regions, to screen for variants in seven of the forty-five exons, considered mutational hot-spots. The aim of this work is to expand the study of the MED12 gene to further increase the mutation detection rate, by screening variants in all exons by PCR-amplification followed by Sanger sequencing. Preliminary results in our patients revealed the absence of the previously identified recurrent mutations and the detection of several variants with unknown significance. Herein, the pathogenic effect of such variants will be analysed.