Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs*4]; c.2564_2567dupTGTT [p.Leu856Phefs*5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

β-Thalassemia (β-thal) is a genetic disorder, representing a major health problem in Algeria. It is associated with altered lipid levels and a state of oxidative stress that can lead to cardiac complications and premature death. We examined the plasma lipid profile and redox status of 46 patients with β-thal major (β-TM) and β-thal intermedia (β-TI) compared to 36 healthy subjects. Plasma lipids including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were investigated. Oxidative status was evaluated by measuring malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) activity. The potential relationships between these parameters and the hemoglobin (Hb) blood concentrations, serum ferritin, duration and frequency of transfusion, splenectomy as well as age, were examined. Our data indicated that the study patients were under increased state of oxidative stress associated with hypertriglyceridemia, and hypocholesterolemia. The CAT activity was negatively correlated with Hb concentration and LDL-C/TG ratio and positively with years of transfusion. The elevated TC/HDL-C ratio particularly in β-TM patients who were younger, correlated positively with ferritinemia and triglyceride levels and suggested an increased coronary risk. This heightened risk state should lead to the inclusion of this index (TC/HDL-C) in clinical management, particularly in splenectomized patients.

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This study concerns the molecular characterization of beta-thalassemia (beta-thal) alleles in 210 chromosomes. In the studied population, mutations were detected in 98% of the beta-thalassemic chromosomes. Twenty-one molecular defects have been found, where the five dominant mutations, IVS-I-110 (G>A), nonsense mutation at codon 39 (C>T), the frameshift codon (FSC) 6 (-A), IVS-I-1 (G>A), and IVS-I-6 (T>C), account for 80% of the independent chromosomes. Among the remaining alleles, 16 different mutations were identified, half of them being described for the first time in Algeria. These include the -101 (C>T) and the -90 (C>T) mutations in the distal and proximal promoter elements, respectively, the FSC 8 (-AA), IVS-I-5 (G>T), IVS-I-128 (T>G), FSC 47 (+A), IVS-II-1 (G>A), and the substitution in the polyadenylation signal (poly A) site AATAAA>AATGAA. Haplotype analyses on rare variants were performed. The possible origin of these mutations either by founder effect or by migrations is discussed, and raises the question of an adequate strategy to be used adapted to socio-economical status.

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