Sodium leak channel, nonselective (NALCN) is a voltage-independent and cation-nonselective channel that is mainly responsible for the leaky sodium transport across neuronal membranes and controls neuronal excitability. Although NALCN variants have been conflictingly reported to be in linkage disequilibrium with schizophrenia and bipolar disorder, to our knowledge, no mutations have been reported to date for any inherited disorders. Using linkage, SNP-based homozygosity mapping, targeted sequencing, and confirmatory exome sequencing, we identified two mutations, one missense and one nonsense, in NALCN in two unrelated families. The mutations cause an autosomal-recessive syndrome characterized by subtle facial dysmorphism, variable degrees of hypotonia, speech impairment, chronic constipation, and intellectual disability. Furthermore, one of the families pursued preimplantation genetic diagnosis on the basis of the results from this study, and the mother recently delivered healthy twins, a boy and a girl, with no symptoms of hypotonia, which was present in all the affected children at birth. Hence, the two families we describe here represent instances of loss of function in human NALCN.

Our data demonstrate that ISCA2 deficiency leads to a hereditary mitochondrial neurodegenerative white matter disease in infancy.

DEAF1 encodes a transcriptional binding factor and is a regulator of serotonin receptor 1A. Its protein has a significant expression in the neurons of different brain regions and is involved in early embryonic development. In addition, its role in neural tube development is evident from the knockout mouse as many homozygotes have exencephaly. Heterozygous mutations of this gene have been linked to intellectual disability in addition to the gene's involvement in major depression, suicidal tendencies, and panic disorder. In this clinical report, we describe two children from a consanguineous family with intellectual disability, microcephaly, and hypotonia. The brain MRI of both patients showed bilateral and symmetrical white matter abnormalities, and one of the patients had a seizure disorder. Using whole exome sequencing combined with homozygosity mapping, a homozygous p.R226W (c.676C>T) mutation in DEAF1 was found in both patients. Furthermore, sequencing analysis confirmed complete segregation in tested family members and absence of the mutation in control cohort (n = 650). The mutation is located in a highly conserved structural domain that mediates DNA binding and therefore regulates transcriptional activity of its target molecules. This study indicates, for the first time to our knowledge, a hereditary role of DEAF1 in white matter abnormalities, microcephaly and syndromic intellectual disability.

(Kv1.4) is implicated in a novel syndrome characterised by striatal thinning, congenital cataract and attention deficit hyperactivity disorder. Our study highlights potassium channels' role in ocular and neuronal genetics.

Mutations in ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) lead to autosomal recessive periventricular heterotopia (PH). To date, 11 mutations, (six missense mutations, one splicing mutation, one small deletion, two small insertions, and one small deletion/insertion) have been reported. Assessing ARFGEF2 mutations will provide a holistic overview of PH. This retrospective study was conducted in 2016 at King Faisal Specialist Hospital and Research Center. For the index patient, magnetic resonance imaging studies revealed a symmetrical focal hyperintensity involving the putamen bilaterally and the inner aspect of the globus pallidus. After family members were genotyped, an autozygosity analysis was performed, followed by exome sequencing of the index patient; A comprehensive filtering approach based on the loss of heterozygosity (LOH) was used to identify variants in phenotypically relevant genes. We report a consanguineous family with two affected individuals, a boy and a girl, with a history of microcephaly, global developmental delay, intellectual disability, myoclonic seizure, and dystonia. The patients carried a novel nonsense mutation (c.3974G>A, p. Trp1325*) in the Armadillo-type fold domain of ARFGEF2. These findings extend our understanding of the phenotypegenotype correlations for ARFGEF2 mutations.