A number sign (#) is used with this entry because of evidence that Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1) 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 Lodder-Merla syndrome type 2 with developmental delay and with or without cardiac arrhythmia (LDMLS2; 617182), a less severe disorder with overlapping features.

Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1) 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).

Genotype-Phenotype Correlation

A direct correlation has been noted between the type of GNB5 variant and the severity of the related phenotype. Individuals with missense variants, both in homozygous or compound heterozygous states (LDMLS2), present with a less severe/moderate phenotype characterized mainly by sinus node dysfunction in combination with mild intellectual disabilities, whereas individuals homozygous for null alleles (LDMLS1) have severe ID, global developmental delay including early infantile developmental and epileptic encephalopathy, hypotonia, as well as sinus node dysfunction (Malerba et al., 2018).

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.

Turkdogan et al. (2017) reported a consanguineous Turkish family in which 5 sibs and a second cousin had low birth weight, early infantile epileptic encephalopathy, severe neurologic developmental delay, nystagmus, retinal degeneration, and cardiac conduction disorder. The proband was a 10-year-old girl (IV.14), a monozygotic twin, who had poor sucking in early infancy requiring admission to the neonatal intensive care unit (NICU), and developed hypomotor seizures at age 6 weeks and epileptic spasms at 4 months. She was hypotonic and did not meet developmental milestones even before seizures began, and was severely autistic with midline hand automatisms and lack of eye contact. On EEG, there were multifocal spikes, disorganized background, and lack of sleep spindles. She had horizontal nystagmus and no eye tracking; ocular evaluation revealed retinal degeneration. ECG and Holter monitoring showed marked sinus arrhythmia with multiple sinus pauses up to 4.5 seconds; further evaluation for pacemaker implantation was declined by the parents. The proband had 4 affected sibs who died in childhood, including her twin sister (IV.13) and an older brother (IV.11) who died suddenly at ages 8 months and 7 months, respectively, during periods when their seizures were well managed, suggesting that sinus node dysfunction was likely the cause of sudden death. An older sister (IV.8) died with severe acute gastroenteritis at 5.5 months of age, and another brother (IV.12) died at age 7 years of multiple organ failure; autopsy reports were not available for these patients. A similarly affected second cousin (V.1) was a 2-year-old boy in whom cardiac evaluation showed sinus bradycardia and pauses up to 3.3 seconds; transesophageal evaluation and pacemaker implantation were declined by his parents.

Vernon et al. (2018) studied a 2-year-old boy who was nonverbal, unable to sit independently, and had minimal voluntary movements. He had central hypotonia and intermittent extremity hypertonia. At birth he was admitted to the NICU for respiratory distress, periodic breathing, and bradycardia. He had laryngomalacia, hypertonia, and clenched hands. Upbeat nystagmus was noted at 3 months, and ERGs showed severely reduced cone and rod function. He had left-sided hearing loss, and brain MRI showed a thin corpus callosum. EEG at 17 months showed high-voltage cortical activity, with multifocal sharp waves in the posterior parietal areas. No frank seizures were documented. Sleep ECG at age 4 months showed sinus arrhythmia with sinus pauses of up to 3 seconds, and Holter monitor at 17 months of age showed sinus pauses as long as 3.1 seconds, with atrial, junctional, and ventricular escape beats following the pauses. He underwent pacemaker placement at age 22 months.

Shao et al. (2020) reported a 3-year-old girl of South Asian descent who developed nystagmus at age 4 months, then experienced status epilepticus at 6 months of age and was also diagnosed with severe bradycardia. Further evaluation revealed global developmental delay, hypotonia, and central sleep apnea. On ocular examination, the proband fixed and followed light. Funduscopy showed mild bilateral temporal disc pallor; macular optical coherence tomography was normal. Electroretinography was consistent with both cone and rod phototransduction recovery deficits, as well as severe rod ON-bipolar cell dysfunction. The authors stated that this represented a unique dual retinal signaling deficit, with features reminiscent of bradyopsia (see 608415) and rod ON-bipolar deficit.

Poke et al. (2019) reviewed the seizure phenotypes experienced by 9 patients from 7 families with LDMLS1, including 5 new and 4 previously reported patients. Epileptic spasms were the most frequent seizure type, occurring in 8 of 9 patients, and began between the ages of 2 months and 3 years (median age, 3 months). Focal seizures preceded the spasms in 3 patients, with onset at 7 days, 11 days, and 4 months of age, and 1 child presented with convulsive status epilepticus at age 6 months. Multiple seizure types were observed in the patients, including focal, tonic-clonic, and tonic. EEG showed burst suppression in 3 children, hypsarrhythmia in 3, and transition from burst suppression to hypsarrhythmia in 1. Background slowing was present in all after age 3 years. MRI was normal in 5 patients; 1 patient showed mild cerebellar atrophy, another had mild ventricular asymmetry, another had long posterior corpus callosum, and 1 showed cerebral atrophy. All 9 had developmental delay prior to seizure onset, and ultimately experienced profound impairment without regression. All exhibited hypotonia, and contractures developed in 2 older patients. Neonatal sinus bradycardia was present in 8 patients, with documented pauses ranging from 2.8 to 6.9 seconds in 4 of them; ECG was reported to be normal in the remaining child. The authors concluded that GNB5-associated developmental and epileptic encephalopathy (DEE) is distinctive and recognizable, characterized by focal seizures, epileptic spasms, and profound impairment, with neonatal cardiac manifestations in some patients.

Yazdani et al. (2020) reported 2 Pakistani brothers with LDMLS1, 18 and 22 years of age, who had severe global cognitive and motor delay (nonverbal and no purposeful movements) as well as seizures during sleep, sick sinus syndrome with frequent pauses, and cortical blindness. The older brother exhibited slow developmental progress until 1 year of age, after which he regressed, progressively losing almost all cognitive, speech, gross motor, and fine motor function. The authors noted some differences in clinical presentation of the brothers compared to previously reported patients, including early diagnosis of complete central blindness and oculomotor dysfunction rather than nystagmus and retinal disease, and severe truncal and limb spasticity rather than hypotonia. In addition, the severity of the seizure disorder appeared to correlate with the severity of their clinical presentation, with the more severely affected older brother continuing to require treatment for seizures, whereas the younger brother no longer had obvious clinical seizures.

Tang et al. (2020) reported a 6-month-old Han Chinese boy who presented with seizures and paroxysmal cyanosis. The infant exhibited obtundation status and developmental delay (developmental age, 1.7 months). Seizures occurred frequently, accompanied by involuntary limb twitches, both eyes turning up, and cyanosis of the lips. Electrocardiography showed a heart rate varying between 254 bpm and 30 bpm. He was diagnosed with neurodevelopmental delay and Adams-Stokes syndrome.

The transmission pattern of LDMLS1 in the families reported by Lodder et al. (2016) was consistent with autosomal recessive inheritance.

1n 6 patients from 4 unrelated families with LDMLS1, 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 (LDMLS2), suggesting a genotype/phenotype correlation.

In a consanguineous Turkish family in which 5 sibs and their second cousin had LDMLS1, Turkdogan et al. (2017) performed whole-exome sequencing (WES) and identified homozygosity for a 1-bp deletion in the GNB5 gene (604447.0007) that segregated fully with disease in the family.

In a 2-year-old boy with severe developmental delay and bradycardia, Vernon et al. (2018) identified compound heterozygosity for a 5-bp deletion (604447.0008) and a missense mutation (R246Q; 604447.0009) in the GNB5 gene. The variants, each inherited from an unaffected parent, were confirmed by Sanger sequencing.

By WES in a 3-year-old girl of South Asian descent with global developmental delay, seizures, severe bradycardia, and retinopathy, Shao et al. (2020) identified homozygosity for a nonsense mutation in the GNB5 gene (Y344X; 604447.0010).

In 5 children from 4 families with LDMLS1, Poke et al. (2019) identified homozygosity for mutations in the GNB5 gene (see, e.g., 604447.0005, 604447.0010, and 604447.0011). The variants segregated with disease in all families and were either not found or were present at very low minor allele frequency in public variant databases.

In 2 Pakistani brothers, 18 and 22 years of age, with severe global cognitive and motor delay, nocturnal seizures, cortical visual impairment, and sick sinus syndrome, Yazdani et al. (2020) performed exome sequencing and identified homozygosity for the previously reported Y344X mutation (604447.0005) in the GNB5 gene. Their mother was heterozygous for the mutation; DNA was unavailable from their father.

In a 6-month-old Han Chinese boy with LDMLS1 and his unaffected nonconsanguineous parents, Tang et al. (2020) performed trio exome sequencing and identified compound heterozygosity for a previously reported nonsense mutation (Y344X; 604447.0010) and a missense mutation (C153Y; 604447.0012). The missense substitution was inherited from his mother, whereas the nonsense mutation arose de novo. Neither was found in public variant databases.

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.