Gnb5-related intellectual disability-cardiac arrhythmia syndrome(IDDCA; LDMLS1)

MedGen UID:: 1800300
•Concept ID:: C5568877
•: Disease or Syndrome

Synonyms:	Intellectual developmental disorder with cardiac arrhythmia; LODDER-MERLA SYNDROME, TYPE 1, WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CARDIAC ARRHYTHMIA
SNOMED CT:	GNB5-related intellectual disability, cardiac arrhythmia syndrome (1186711002); G protein subunit beta 5-related intellectual disability, cardiac arrhythmia syndrome (1186711002)
Modes of inheritance:	Autosomal recessive inheritance MedGen UID: 141025 •Concept ID: C0441748 • Intellectual Product Source: Orphanet A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	GNB5 (15q21.2)

Monarch Initiative:	MONDO:0014953
OMIM®:	617173
Orphanet:	ORPHA542306

Disease characteristics

Excerpted from the GeneReview: GNB5-Related Neurodevelopmental Disorder

GNB5-related neurodevelopmental disorder (GNB5-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of GNB5-NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased. [from GeneReviews]

Authors:
Gemma Poke | Lynette Grant Sadleir | Giuseppe Merla, et. al. view full author information

Additional description

From OMIM
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). http://www.omim.org/entry/617173

Clinical features

From HPO

Sick sinus syndrome

MedGen UID:: 20749
•Concept ID:: C0037052
•: Disease or Syndrome

An abnormality involving the generation of the action potential by the sinus node and is characterized by an atrial rate inappropriate for physiological requirements. Manifestations include severe sinus bradycardia, sinus pauses or arrest, sinus node exit block, chronic atrial tachyarrhythmias, alternating periods of atrial bradyarrhythmias and tachyarrhythmias, and inappropriate responses of heart rate during exercise or stress.

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Bradycardia

MedGen UID:: 140901
•Concept ID:: C0428977
•: Finding

A slower than normal heart rate (in adults, slower than 60 beats per minute).

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Gastroesophageal reflux

MedGen UID:: 1368658
•Concept ID:: C4317146
•: Finding

A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.

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Seizure

MedGen UID:: 20693
•Concept ID:: C0036572
•: Sign or Symptom

A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

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Delayed speech and language development

MedGen UID:: 105318
•Concept ID:: C0454644
•: Finding

A degree of language development that is significantly below the norm for a child of a specified age.

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Global developmental delay

MedGen UID:: 107838
•Concept ID:: C0557874
•: Finding

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.

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Intellectual disability

MedGen UID:: 811461
•Concept ID:: C3714756
•: Mental or Behavioral Dysfunction

Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.

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Hypotonia

MedGen UID:: 10133
•Concept ID:: C0026827
•: Finding

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

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Nystagmus