Intellectual Developmental Disorder With Cardiac Arrhythmia

A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with cardiac arrhythmia (IDDCA) is caused by homozygous or compound heterozygous mutation in the GNB5 gene (604447) on chromosome 15q21.

Biallelic missense mutation in the GNB5 gene can cause language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (LADCI; 617182), a less severe disorder with overlapping features.

Description

Intellectual developmental disorder with cardiac arrhythmia is an autosomal recessive multisystem disorder characterized by delayed psychomotor development, severe intellectual disability with poor or absent speech, and bradycardia and/or cardiac sinus arrhythmias. Additional features include visual abnormalities, seizures, hypotonia, and gastric reflux (summary by Lodder et al., 2016).

Clinical Features

Lodder et al. (2016) reported 6 patients from 4 unrelated families of various ethnic backgrounds with a complex multisystem disorder apparent from infancy or early childhood. The patients ranged in age from 6 to 22 years, and the families originated from Italy, Jordan, Puerto Rico, and India. The patients had delayed psychomotor development with severe intellectual disability, poor or absent speech, severe hypotonia, often without head control, and nystagmus. All also had cardiac abnormalities, most commonly sick sinus syndrome with bradycardia, escape beats, and other arrhythmias in the absence of structural abnormalities, except for a patent foramen ovale in 1 patient. Two sibs had a pacemaker implanted. Visual abnormalities were variable: 2 sibs had retinal degeneration, another patient had no eye contact, and 3 patients had abnormal electroretinograms. Four patients had seizures, including 1 patient with refractory seizures and hypsarrhythmia, and 5 patients had pathologic gastric reflux. Brain imaging was basically normal.

Inheritance

The transmission pattern of IDDCA in the families reported by Lodder et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients from 4 unrelated families with IDDCA, Lodder et al. (2016) identified homozygous or compound heterozygous truncating mutations in the GNB5 gene (604447.0001-604447.0005). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants were not performed; studies of patient cells, performed only in 1 family (family A) with compound heterozygous truncating variants, demonstrated that both alleles were subject to nonsense-mediated mRNA, consistent with a complete loss of function. These patients were part of a cohort of 9 patients from 6 families who were found to have GNB5 mutations: those with truncating mutations had a more severe phenotype than those with a missense mutation (LADCI), suggesting a genotype/phenotype correlation.

Animal Model

Lodder et al. (2016) used CRISPR/Cas9 genome editing to generate complete loss of gnb5 function in zebrafish; mutant zebrafish had impaired swimming activity, remained small, and died 7 to 14 days postfertilization, likely due to an inability to feed. Treatment of mutant larvae with carbachol, a parasympathomimetic compound that activates the GNB5/RGS/GIRK (G protein-coupled inward rectifier potassium) channel pathway, resulted in a strong decrease in heart rate compared to controls. Treatment with a sympathetic agonist resulted in an increased heart rate similar to controls. These findings indicated that loss of gnb5 caused a loss of negative regulation of the cardiac GIRK channel and parasympathetic control, without effects on sympathetic control. Mutant larvae were predominantly unresponsive to repeated tactile stimulation, apparently due to neurologic deficits, not muscle dysfunction, and showed impaired optokinetic responses, also with normal eye muscle function. The findings indicated that Gnb5 is important for neuronal signaling and autonomic function.