The MED13L haploinsufficiency syndrome associated with de novo nonsense variant (P.GLN1981*)

Mental retardation and distinctive facial features with or without cardiac defects (MRFACD) syndrome is a type of syndromic intellectual disability (ID) caused by heterozygous variants in the MED13L gene resulting in a loss-of-function (LoF), or less often in missense mutations affecting the MED13L protein.1 It appears that the MED13L gene mutations are one of the most frequent causes of ID.2 Previously, pathogenic variants of the MED13L gene were associated with dextro-looped transposition of the great arteries and ID.3 However, additional studies reveal that cardiac disorders are not leading symptoms caused by the MED13L gene defects, and both missense and LoF variants can cause MRFACD.4 In this study, we present a new case of the MRFACD syndrome in a Polish patient with severe ID, DD and dysmorphic features, which overlap with previous reports, as well as uncommon findings like lack of speech, strabismus and self-destructive behaviour.

Whole exome sequencing identified a heterozygous single nucleotide substitution c.5941C>T (NM_015335.4) at exon 27 in the MED13L gene. This substitution is predicted to cause a premature translational stop codon p.(Gln1981*), affecting the last 229 residues and N-terminal domain of the protein. The variant was not found in the 1000 Genomes, Exome Variant Server and gnomAD databases as well as in our own database. No other phenotypically relevant pathogenic/potentially pathogenic variants were identified in our patient.

In silico analysis performed with MutationTaster indicated that the c.5941C>T substitution is a disease-causing variant and is predicted to cause nonsense-mediated decay (NMD). This variant is also predicted to be deleterious by both CADD and FATHMM (score: 46.00 and 0.9922 with accuracy: 0.70 and 0.78, respectively). Additional analysis with the Alamut software predicted possible NMD of the mRNA.

Further Sanger sequencing of the c.5941C>T variant in the patient’s family confirmed the absence of mutation in both parents, indicating its de novo origin and thus supporting its pathogenicity (Fig. S1A in Supplementary Material).

MRFACD is a genetic disorder caused by molecular defect of the MED13L gene. To date, more than 70 patients with mutations in this gene have been identified, mostly in the past 2 years.5 It appears that the MED13L gene mutations are one of the most frequent causes of syndromic ID; however, in our in-house database consisting of over 700 patients with various neurodevelopmental disorders, ID and specific dysmorphic features, we found only one that caused mutation.2 In all the cases, the identified single point variants in the MED13L gene predominated the loss-of function mutations (76% of all cases).5

In this study, we describe a patient with severe ID, developmental delay, absence of speech, dysmorphic features and hypotonia. Due to the presence of the LARGE1 gene deletion identified by aCGH, congenital muscular dystrophy-dystroglycanopathy with mental retardation (OMIM # 608840) was first suspected in the patient. However, NGS analysis did not confirm the presence of additional pathogenic variants in the preserved copy of the LARGE1 gene. Further investigation revealed de novo deleterious c.5941C>T variant in the MED13L gene, which is predicted to cause NMD of the transcript as a result of premature termination codon activation p.(Gln1981*).

Recently, Torring et al. have summarized clinical presentation of the disease in 69 patients with the MED13L gene mutations. Most of the disease features were present in our patient (Table 1), including common symptoms, but also less frequent findings like completely absent speech, self-destructive behaviour and strabismus. To our knowledge, there was only one case described by Muncke et al. with nearly absent speech in a girl aged 7 years with serious cardiac defect and a de novo heterozygous balanced translocation that interrupted the MED13L gene on chromosome 12q24.3

Hypotonia, speech delay and brain abnormalities in MRI are quite common among these patients (70%, 99% and 45%, respectively). Also, dysmorphic features such as bulbous nasal tip, depressed/flat nasal bridge, upslanting palpebral fissures and abnormal chin have been previously reported in patients with the MED13L haploinsufficiency syndrome.

Our findings support the conclusion that the phenotype of patients with loss-of-function variants in the MED13L gene could be a clinically recognizable MRFACD syndrome, especially when ID is accompanied by development and speech delay and specific dysmorphic features. We further define the phenotype caused by deleterious variants of the MED13L gene, broadening the phenotypic spectrum with uncommon findings of absent speech, strabismus, self-destructive behaviour, and constipations and confirm low penetration of cardiac abnormalities in patients with MRFACD syndrome. However, due to some similarity to other syndromes with ID such as FG syndrome caused by MED12 mutation, 1p36 deletion syndrome or 22q11.2 deletion syndrome and proved variable clinical expression, the use of NGS is recommended for disease differential diagnosis.6, 7