TY - JOUR
T1 - Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome
AU - Cafiero, Concetta
AU - Marangi, Giuseppe
AU - Orteschi, Daniela
AU - Ali, Marwan
AU - Asaro, Alessia
AU - Ponzi, Emanuela
AU - Moncada, Alice
AU - Ricciardi, Stefania
AU - Murdolo, Marina
AU - Mancano, Giorgia
AU - Contaldo, Ilaria
AU - Leuzzi, Vincenzo
AU - Battaglia, Domenica Immacolata
AU - Mercuri, Eugenio Maria
AU - Slavotinek, Anne M.
AU - Zollino, Marcella
PY - 2015
Y1 - 2015
N2 - MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype.European Journal of Human Genetics advance online publication, 25 February 2015; doi:10.1038/ejhg.2015.19.
AB - MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype.European Journal of Human Genetics advance online publication, 25 February 2015; doi:10.1038/ejhg.2015.19.
KW - MED13L
KW - MED13L
UR - http://hdl.handle.net/10807/66218
U2 - 10.1038/ejhg.2015.19
DO - 10.1038/ejhg.2015.19
M3 - Article
SN - 1018-4813
SP - 1499
EP - 1504
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
ER -