Mental Retardation And Distinctive Facial Features With Or Without Cardiac Defects

A number sign (#) is used with this entry because of evidence that mental retardation and distinctive facial features with or without cardiac defects (MRFACD) is caused by heterozygous mutation in the MED13L gene (608771) on chromosome 12q24.

Heterozygous missense mutation in the MED13L gene can cause isolated dextro-looped transposition of the great arteries (DTGA1; 608808).

Description

Mental retardation and distinctive facial features with or without cardiac defects (MRFACD) is an autosomal dominant, complex syndromic neurodevelopmental disorder characterized by delayed psychomotor development, poor speech acquisition, distinctive dysmorphic facial features, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries (summary by Adegbola et al., 2015).

Clinical Features

Asadollahi et al. (2013) reported 2 unrelated girls with facial dysmorphism and conotruncal congenital heart defects, including total anomalous pulmonary venous connection, ventricular septal defect, and tetralogy of Fallot.

Redin et al. (2014) reported an 18-year-old man with moderate intellectual disability, delayed motor development, hypotonia, dysarthria, and dysmorphic facial features, including round face, hypertelorism, everted lower lip, low-set ears, and coloboma. Echocardiography was normal.

Van Haelst et al. (2015) reported 2 unrelated children with delayed psychomotor development, poor speech, truncal hypotonia, and a hypotonic open-mouth appearance. One had mildly poor growth and dysmorphic features, including a slightly asymmetric face with short, upslanted palpebral fissures, flat nasal bridge with bulbous nasal tip, macroglossia, bilateral accessory nipples, and clubfoot. Cardiac examination was normal. The other patient had small eyelids, mild retrognathia, broad nasal bridge, and a persistent foramen ovale. Van Haelst et al. (2015) commented on the reduced penetrance of severe cardiac abnormalities in these patients.

Adegbola et al. (2015) reported 6 unrelated children with delayed psychomotor development apparent since infancy, mild to moderate intellectual disability, and delayed speech. Most had hypotonia, and 3 had ataxia. Common dysmorphic features included broad prominent forehead, bitemporal narrowing, low-set ears, upslanting palpebral fissures, flat nasal root with broad nasal tip, and macrostomia with an open-mouth appearance. Less common features included short neck, hypertelorism, high-arched palate, triangular face, hypermetropia, cryptorchidism, clinodactyly, and recurrent infections. Several patients had autistic features. None had a complex congenital heart defect, although 1 had persistent patent foramen ovale.

Cafiero et al. (2015) reported 3 unrelated children with delayed psychomotor development and common dysmorphic facial features, including brachycephaly, high forehead, round face, horizontal eyebrows with synophrys, upslanting palpebral fissures, depressed nasal bridge with bulbous nasal tip, prognathism, and large ears with thickened helices. One patient had speech delay and hypotonia, 2 had ataxia, and 1 had seizures. Only 1 patient had a patent foramen ovale. Cafiero et al. (2015) noted phenotypic similarities to the 1p36 deletion syndrome (607872).

Cytogenetics

In a 7-year-old girl with delayed psychomotor development and complex congenital heart malformations, Muncke et al. (2003) found a de novo heterozygous balanced translocation t(12,17)(q24.1;q21) that interrupted the MED13L gene on chromosome 12q24; no genes were identified in the breakpoint region on chromosome 17. The patient had postnatal microcephaly, delayed motor development with ataxia, and mental retardation with nearly absent speech. Cardiac defects included TGA, a ventricular septal defect, open foramen ovale, and mild coarctation of the aorta.

In a girl with clinically insignificant perimembranous ventricular septal defect, mild hypotonia, and mild developmental delay, Asadollahi et al. (2013) identified a heterozygous 1-Mb de novo triplication involving the entire MED13L gene as well as several nonprotein-coding RNA genes and the MAP1LC3B2 gene.

Utami et al. (2014) reported a 14-year-old girl with delayed development, moderate intellectual disability and very poor speech associated with a de novo heterozygous balanced translocation t(12;19)(q24;q12) that interrupted the MED13L gene. She also had dysmorphic facial features, including cleft palate, glossoptosis, retrognathia, hypertelorism, flat philtrum, broad nasal bridge, bulbous nose, strabismus, and hirsutism. Additional features included multiple limb contractures, camptodactyly, foot deformities, absence seizures, and global cerebral atrophy on brain imaging. The breakpoint on 19q12 did not disrupt any coding genes. Patient cells showed decreased mRNA and protein levels of MED13L compared to controls, suggesting haploinsufficiency.

In a girl with a clinically insignificant perimembranous ventricular septal defect, mild hypotonia, and mild developmental delay, Asadollahi et al. (2013) identified a heterozygous 1-Mb de novo triplication involving the entire MED13L gene as well as several nonprotein-coding RNA genes and the MAP1LC3B2 gene.

Adegbola et al. (2015) reported 2 unrelated children with a heterozygous duplication (3.0 Mb) or deletion (1.9 Mb) that involved several additional genes. One patient had a patent foramen ovale and the other had a ventricular septal defect, but neither patient had any other complex cardiac malformations. The duplication was inherited from a mother with similar craniofacial features, whereas the 1.9-Mb deletion occurred de novo.

Molecular Genetics

In 2 unrelated girls with MRFACD, Asadollahi et al. (2013) identified heterozygosity for 2 different de novo frameshift intragenic deletions within the MED13L gene on chromosome 12q24. The first patient had a 17-kb deletion encompassing exon 2 of MED13L, whereas the second had a 115-kb deletion encompassing exons 3 and 4. Functional studies and studies of patient cells were not performed, but the authors postulated haploinsufficiency.

In a 7-year-old girl with delayed psychomotor development and nonsyndromic intellectual disability, Hamdan et al. (2014) identified a de novo heterozygous truncating mutation in the MED13L gene (608771.0004). Cardiac malformations were not reported. The patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing.

In an 18-year-old man with MRFACD, Redin et al. (2014) identified a de novo heterozygous truncating mutation in the MED13L gene (608771.0005). The patient was part of a cohort of 106 patients with intellectual disability who underwent targeted high-throughput sequencing of 217 genes.

In 2 unrelated children with MRFACD, van Haelst et al. (2015) identified 2 different de novo heterozygous mutations in the MED13L gene (608771.0006 and 608771.0007) that were predicted to result in haploinsufficiency. Functional studies of the variants and studies of patient cells were not performed.

In 6 unrelated children with MRFACD, Adegbola et al. (2015) identified 5 different de novo heterozygous intragenic deletions and 1 intragenic duplication within the MED13L gene (see, e.g., 608771.0008 and 608771.0009). The mutations were identified by array CGH or whole-exome sequencing. All were predicted to disrupt the gene, resulting in haploinsufficiency, but functional studies and studies on patient cells were not performed.

In 3 unrelated patients with MRFACD, Cafiero et al. (2015) identified 3 different de novo heterozygous mutations in the MED13L gene (see, e.g., 608771.0010 and 608771.0011). All mutations were predicted to result in a truncated protein and haploinsufficiency, but functional studies and studies on patient cells were not performed.