Table 2.
Genes with de novo CNV alterations in the proband that are functionally associated to neurological phenotypes
| 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 [25–29] |
| SLC17A5 (604322) | 6q13 | Solute Carrier Family 17 Member 5 | Affects membrane potential-driven aspartate and glutamate transport into synaptic vesicles [30–32] 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 [37–40] | Altered neuronal polarization and depolarization [37–40] |
| 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 [44–46] |
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] |
| 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 [63–69] |