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

Abstract

Background Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

Mapping combinatorial expression of non-clustered protocadherins in the developing brain identifies novel PCDH19-mediated cell adhesion properties

“…We have identified prevalent expression of Pcdh19+9 and Pcdh19+1 in the hippocampus and cortex which correlates with the relatively high expression of these proteins in the brain. Considering that PCDH9 and 19 are found in excitatory neuron synapses and variants in their cognate genes have been linked to neurodevelopmental disorders [9,29,38], it is possible that they control similar neurocircuit processes. In contrast, besides the higher expression of Pcdh1 in the mouse brain, mutations in PCDH1 have been exclusively linked to respiratory disorders in humans [39] suggesting a potential auxiliary cell adhesion role in the CNS, perhaps through other PCDHs.…”

Novel NALCN variant linked to temporal lobe epilepsy

“…Our search of the literature identified 11 patients with seizures harboring NALCN variants (Table 1). All had IHPRF (7), CLIFAHDD (2) or infantile neuraxonal dystrophy (INAD) (2); seizures were never the mode of presentation (Al‐Sayed et al, 2013; Angius et al, 2018; Chong et al, 2015; Gal et al, 2016; García‐Hernández et al, 2021; Köroğlu et al, 2013). In contrast, our two cases only had focal epilepsy without intellectual disability nor any feature remotely resembling IHPRF, CLIFAHDD or INAD.…”

“…Mutations in the NALCN gene have been reported in patients with infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF; MIM 615419) and congenital contractures of the limbs and face with hypotonia and developmental delay (CLIFAHDD syndrome; MIM 616266) (Angius et al, 2018). A handful of patients with developmental delay/intellectual disability and epilepsy have also been reported (Al‐Sayed et al, 2013; Angius et al, 2018; Chong et al, 2015; Gal et al, 2016; García‐Hernández et al, 2021; Köroğlu et al, 2013). Herein, we report a father and a son featuring focal epilepsy without intellectual disability, expanding the spectrum of NALCN‐related disorders.…”

Identification of SNPs and Candidate Genes for Milk Production Ability in Yorkshire Pigs

“…It was reported that NAV2 was associated with hyperlipidemia ( Sun et al, 2018a ). ANO3 was associated with dystonia and motor neuron dysfunction ( García-Hernández et al, 2021 ). The glycoprotein MUC15 was initially isolated from the bovine milk fat globule membrane and had a potential physiological function in signal transduction ( Pallesen et al, 2008 ).…”