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

 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]

 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]