Intellectual Developmental Disorder With Cardiac Defects And Dysmorphic Facies

A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF) is caused by homozygous or compound heterozygous mutation in the TMEM94 gene (618163) on chromosome 17q25.

Description

IDDCDF is an autosomal recessive syndromic neurodevelopmental disorder characterized by globally impaired development with intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Additional features, such as distal skeletal anomalies, may also be observed (summary by Stephen et al., 2018).

Clinical Features

Stephen et al. (2018) reported 10 patients from 6 unrelated families with a similar syndromic neurodevelopmental disorder. The families were of different ethnic origins, but most were consanguineous and of Middle Eastern descent. The patients ranged in age from 3 to 24 years, and all had global developmental delay apparent from infancy or early childhood, with mild to moderate impaired intellectual development, learning disabilities, speech delay, and mildly delayed walking. Many attended special schools; IQ of 1 patient at age 16 was 58. All but 1 of the patients presented in infancy with variable congenital heart defects, including tetralogy of Fallot, atrial and ventricular septal defects, patent foramen ovale, patent ductus arteriosus, hypoplastic pulmonary valve or pulmonary atresia, and double outlet right ventricle. Dysmorphic features included triangular face with pointed chin, short nose with anteverted nares, flat nasal bridge, deep-set eyes, hypertelorism, long philtrum, thin upper lip, low-set or dysmorphic ears, highly arched eyebrows, and synophrys or hypertrichosis. Some patients had mild myopia or strabismus, and some had somatic overgrowth and large head circumference. About half of patients had skeletal anomalies, such as long or overlapping fingers or toes, cutaneous syndactyly, and scoliosis. Less common features observed in only 1 or 2 patients included seizures, pectus abnormalities, hypotonia, feeding or respiratory difficulties, hypospadias, and cryptorchidism. Brain imaging, performed in a few patients, showed nonspecific abnormalities, such as Chiari I malformation (1 patient), delayed myelination, and white matter signal abnormalities.

Inheritance

The transmission pattern of IDDCDF in the families reported by Stephen et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 10 patients from 6 unrelated families with IDDCDF, Stephen et al. (2018) identified homozygous or compound heterozygous nonsense, frameshift, or splice site mutations (see, e.g., 618163.0001-618163.0005). All the mutations were predicted or demonstrated to result in truncated proteins lacking the highly conserved C-terminal domain including cation P-type ATPase domains. Analysis of cells from patients from 2 unrelated families showed significantly decreased TMEM94 expression, consistent with a loss of function. Global transcriptome profiling of cells from 1 family showed dysregulation of genes involved in cell growth, proliferation, and survival that were predicted to affect several organ systems involved in the phenotype. The patients were ascertained through collaborative research efforts and matchmaking platforms, and the mutations, which were found by a combination of homozygosity mapping and whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Several of the affected individuals were found to have homozygous variants of unknown significance in other genes, including those known to cause recessively inherited neurodevelopmental disorders, but these variants were not considered to be the primary genetic cause of the disorder.

Animal Model

Stephen et al. (2018) found that homozygous loss of Tmem94 in mice was embryonic lethal and led to craniofacial defects, cardiac abnormalities, and abnormal neuronal migration in the central nervous system.