Report of a de novo c.2605C > T (p.Pro869Ser) change in the MED13L gene and review of the literature for MED13L-related intellectual disability

Abstract

Background MED13L-related intellectual disability is a new syndrome that is characterized by intellectual disability (ID), motor developmental delay, speech impairment, hypotonia and facial dysmorphism. Both the MED13L haploinsufficiency mutation and missense mutation were reported to be causative. It has also been reported that patients carrying missense mutations have more frequent epilepsy and show a more severe phenotype. Case presentation We report a child with ID, speech impairment, severe motor developmental delay, facial deformity, hypotonia, muscular atrophy, scoliosis, odontoprisis, abnormal electroencephalogram (EEG), and congenital ureteropelvic junction obstruction (UPJO) combined with high ureter attachment. We used whole-exome sequencing (WES) to detect the genetic aberration of the child and found a de novo mutation, c.2605C > T (p.Pro869Ser), in the MED13L gene. Neither of her parents carried the mutation. Additionally, we review the literature and summarize the phenotypes and features of reported missense mutations. After reviewing the literature, approximately 17 missense mutations in 20 patients have been reported thus far. For 18 patients (including our case) whose clinical manifestations were provided, 100% of the patients had ID or developmental delay (DD). A total of 88.9, 83.3 and 66.7% of the patients had speech impairment, delayed milestones and hypotonia, respectively. A total of 83.3% of the patients exhibited craniofacial deformity or other dysmorphic features. Behavioral difficulties and autistic features were observed in 55.6% of the patients. Cardiac anomalies were seen in only 27.8% of the patients. Of these patients, 44.4% had epileptic seizures. Of the 17 mutations, 2 were located in the N-terminal domain, 8 were located in the C-terminal domain, and 1 was located in an α-helical sequence stretch. One of them was located in the MID domain of the MedPIWI module. Conclusions We report a new patient with a reported missense mutation, c.2605C > T (p.Pro869Ser), who exhibited some infrequent manifestations except common phenotypes, which may broaden the known clinical spectrum. Additionally, by reviewing the literature, we also found that patients with missense mutations have a higher incidence of seizures, MRI abnormalities, autistic features and cardiac anomalies. They also have more severe ID and hypotonia. Our case further demonstrates that Pro869Ser is a hotspot mutation of the MED13L gene.

MED13L-related intellectual disability due to paternal germinal mosaicism

“…MRFACD, MED13L -related intellectual disability syndrome, a recently recognized but well-described congenital malformation, is an intellectual disability syndrome with detailed clinical descriptions available for only 75 reported individuals ( Muncke et al 2003 ; Asadollahi et al 2013 , 2017 ; Redin et al 2014 ; Utami et al 2014 ; Adegbola et al 2015 ; Cafiero et al 2015 ; van Haelst et al 2015 ; Caro-Llopis et al 2016 ; Yamamoto et al 2017 ; Gordon et al 2018 ; Jiménez-Romero et al 2018 ; Smol et al 2018 ; Tørring et al 2019 ; Yi et al 2020 ; Dawidziuk et al 2021 ). A further 14 cases have been identified in the frames of large high-throughput sequencing studies investigating the genetic background of intellectual disability or congenital heart defect ( Musante et al 2004 ; Najmabadi et al 2011 ; Iossifov et al 2012 ; Hamdan et al 2014 ; Iglesias et al 2014 ; Codina-Solà et al 2015 ; Martínez et al 2017; Mullegama et al 2017 ; Aoi et al 2019 ; Ji et al 2020 ; Sabo et al 2020 ; Tian et al 2021 ).…”

Two novel pathogenic variants in MED13L: one familial and one isolated case

“…Further, according to Yi et al . (2020), patients with missense mutations in MED13L also have a more severe phenotype in other aspects, including hypotonia, absent speech and severely delayed motor function, compared with patients with truncating variants. The occurrence of truncating variants involving the entire MED13L gene would lead to the conclusion that the clinical condition is due to haploinsufficiency.…”

“…Both the MED13L haploinsufficiency mutation and missense mutation have been reported to be causative (Yi et al . 2020).…”

Investigação genética da obesidade sindrômica e desenvolvimento de modelos biológicos para estudo da síndrome de Xia-Gibbs

“…MED13L mutations were related to the clinical condition OMIM#616789 (mental retardation and distinctive facial features with or without cardiac defects) and with several types of genetic variants involving MED13L gene: nonsense (Cafiero et al 2015;Caro-Llopis et al 2016), frameshift (Hamdan et al 2014;Redin et al 2014;Adegbola et al 2015;Cafiero et al 2015;Codina-Solà et al 2015;Asadollahi et al 2017;Yamamoto et al 2017), CNV deletion including MED13L (Adegbola et al 2015), CNV duplication including MED13L (Adegbola et al 2015), CNV triplication including MED13L (Asadollahi et al 2013), intragenic CNV deletion (Asadollahi et al 2013;Adegbola et al 2015;van Haelst et al 2015;Yamamoto et al 2017), intragenic CNV duplication (Adegbola et al 2015), disruptive translocation (Muncke et al 2003;Utami et al 2014) and missenses (Gilissen et al 2014;Asadollahi et al 2017;Yi et al 2020). In general, they are cases of heterozygous variants.…”

“…et al 2017). Both the MED13L haploinsufficiency mutation and missense mutation have been reported to be causative (Yi et al 2020).…”