Skip to main content

Table 2 Genes with de novo CNV alterations in the proband that are functionally associated to neurological phenotypes

From: Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

GENE (OMIM) Chromosome Protein Protein functions Associated neuropathology
CNV losses
ATP1A2 (182340) 1q23.2 ATPase Na+/K+ Transporting Subunit Alpha 2 Na+/K+ ATPase maintains electrochemical gradient for electrical excitability of nerve and muscle. Participates in neurotransmitter uptake and muscle contraction [23, 24] Rare forms of epilepsy and seizures [25,26,27,28,29]
SLC17A5 (604322) 6q13 Solute Carrier Family 17 Member 5 Affects membrane potential-driven aspartate and glutamate transport into synaptic vesicles [30,31,32] Required for normal CNS myelination [33, 34]. Pathogenic variants or CNV loss of one allele associated to hypotonia, ataxia, epilepsy, seizures, nystagmus and findings of cerebral and cerebellar atrophy [33]
ELAVL2 (601673) 9p21.3 ELAV Like RNA Binding Protein 2 Neural-specific RNA-binding protein that binds to several 3' UTRs. Expressed in early neuronal progenitors to mature neurons [35] and required for normal neuronal development in the embryonic CNS Alterations in neuronal differentiation and regulates neurodevelopmental and synaptic gene networks [36]
LRRC55 (615213) 11q21.32 Leucine Rich Repeat Containing 55 Subunit modulating gating properties in Ca2+- activated potassium channel BK, and its voltage dependence in the hyperpolarizing direction [37,38,39,40] Altered neuronal polarization and depolarization [37,38,39,40]
PCDH9 (603581) 13q21.32 Protocadherin 9 Ca2+-dependent cell adhesion in neural tissues. Protein involved in signaling at neuronal synaptic junctions [41, 42] Epileptic encephalopathy [43]
NALCN (611549) 13q33.1 Sodium Leak Channel, Non-Selective Voltage-gated Na+ and Ca2+ channels regulating the resting membrane potential and excitability of neurons [44,45,46] NALCN deficiency is associated to channelopathies [47]. NALCN pathogenic variants associated to Neuroaxonal Dystrophy (INAD) patients, severe hypotonia, speech impairment, cognitive delay, epilepsy and mental disability [44, 45, 48, 49]
NALCN associated to dystonia [46, 50]
RYR3 (180903) 15q14 Ryanodine Receptor 3 Presynaptic endoplasmic reticulum ryanodine receptor-mediated Ca2+ release [51, 52]. Involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules
Regulates composition of the protein complex that forms a voltage-independent, nonselective, non-inactivating cation channel permeable to Na+, K+, and Ca2+, which regulates the neuronal background sodium leak conductance [53]
RYR3 haploinsuficiency cooperates SCN1A, implicated in epileps y[54, 55].
CDH13 (601364) 16q23.3 Cadherin 13 Negative regulator of axon growth during neural differentiation [41, 43] Epileptic encephalopathy [43]
ANO3 (610110) 11p14.3 Anoctamine 3 Mutation in this gene exhibited abnormalities in endoplasmic reticulum-dependent calcium signaling, AbnormalCa2+-activated chloride channel [56, 57] ANO3 pathogenic variants have a dominant effect on dystonia [58, 59] and to complex neurological syndrome combining dystonia and myoclonus phenotypes [60, 61]
CNV gains
EFNA5 (601535) 5q21.3 Ephrin A5 Involved in short-range contact-mediated axonal guidance. Prevents axon bundling of cortical neurons with astrocytes [62]  
PCDH19 (300460) Xq22.1 Protocadherin 19 Calcium-dependent cell-adhesion protein primarily expressed in the developing brain [63, 64] PCDH19 pathogenic variants and CNV in epilepsy [63,64,65,66,67,68,69]