Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.

Inherited peripheral neuropathies (IPNs) are a heterogeneous group of disorders of the peripheral nervous system. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease, which constitutes an interesting research focus for neurologists and human geneticists alike. Most cases with CMT manifest with a slowly progressive symmetric distal weakness in the lower limbs that usually begin in the first to the third decade that causes atrophy and foot drop. Deep tendon reflexes are usually absent or reduced. A proven and efficient CMT therapy is yet available and may require different molecules and approaches due to its high clinical and genetic heterogeneity. Several ongoing clinical trials are promising and are mostly focused on the most frequent form, namely CMT Type 1A (CMT1A). Approximately, 60% of patients with CMT can be genetically diagnosed using the most advanced mutation screening techniques that cover approximately 100 IPN genes. Turkey has a 25% consanguineous marriage rate, and nearly 60% genetic diagnosis rate can still be reached when SH3 Domain and Tetratricopeptide Repeat Domain 2, Ganglioside-induced Differentiation-Associated Protein 1, and Histidine Triad Nucleotide Binding Protein 1 genes are also screened along with Myelin Protein Zero and Gap Junction Protein Beta-1 after exclusion of CMT1A duplication in families with probable recessive inheritance. The genetic diagnosis rates in different regions worldwide implicate that the most recent sequencing techniques should be more commonly used for both diagnosis and identification of further CMT genes. Herein, presented our 30 years of experience on genetic diagnosis and management strategies in CMT neuropathy in Turkey and review clinical and genetic features of this group of disorders.

Background and Objectives Inherited peripheral neuropathies (IPNs) are a group of genetic disorders of the peripheral nervous system in which neuropathy is the only or the most predominant clinical feature. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease. Autosomal recessive CMT (ARCMT) is generally more severe than dominant CMT and its genetic basis is poorly understood due to high clinical and genetic diversity. Here, we report clinical and genetic findings from 56 consanguineous Turkish families initially diagnosed with CMT disease. Methods We initially screened the GDAP1 gene in our cohort as it is the most commonly mutated ARCMT gene. Next, whole-exome sequencing and homozygosity mapping based on whole-exome sequencing (HOMWES) analysis was performed. To understand the molecular impact of candidate causative genes, functional analyses were performed in patient primary fibroblasts. Results Biallelic recurrent mutations in the GDAP1 gene have been identified in 6 patients. Whole-exome sequencing and HOMWES analysis revealed 16 recurrent and 13 novel disease-causing alleles in known IPN-related genes and 2 novel candidate genes: 1 for a CMT-like disease and 1 for autosomal recessive cerebellar ataxia with axonal neuropathy. We have achieved a potential genetic diagnosis rate of 62.5% (35/56 families) in our cohort. Considering only the variants that meet the American College for Medical Genetics and Genomics (ACMG) classification as pathogenic or likely pathogenic, the definitive diagnosis rate was 55.35% (31/56 families). Discussion This study paints a genetic landscape of the Turkish ARCMT population and reports additional candidate genes that might help enlighten the mechanism of pathogenesis of the disease.

Charcot–Marie–Tooth neuropathy type 4D (CMT4D) is a rare genetic disorder of the peripheral nervous system caused by biallelic mutations in the N-Myc Downstream Regulated 1 gene (NDRG1). Patients present with an early onset demyelinating peripheral neuropathy causing severe distal muscle weakness and sensory loss, leading to loss of ambulation and progressive sensorineural hearing loss. The disorder was initially described in the Roma community due to a common founder mutation, and only a handful of disease-causing variants have been described in this gene so far. Here, we present genetic and clinical findings from a large Bulgarian cohort of demyelinating CMT patients harboring recurrent and novel variants in the NDRG1 gene. Notably, two splice-site variants are exclusive to Bulgarian Muslims and reside in ancestral haplotypes, suggesting a founder effect. Functional characterization of these novel variants implicates a loss-of-function mechanism due to shorter gene products. Our findings contribute to a deeper understanding of the genetic and clinical heterogeneity of CMT4D and highlight novel founder mutations in the ethnic minority of Bulgarian Muslims.

Hereditary spastic paraplegia (HSP) is among the most genetically diverse of all monogenic diseases. The aim was to analyze the genetic causes of HSP among adult Serbian patients. The study comprised 74 patients from 65 families clinically diagnosed with HSP during a nine-year prospective period. A panel of thirteen genes was analyzed: L1CAM (SPG1), PLP1 (SPG2), ATL1 (SPG3A), SPAST (SPG4), CYP7B1 (SPG5A), SPG7 (SPG7), KIF5A (SPG10), SPG11 (SPG11), ZYFVE26 (SPG15), REEP1 (SPG31), ATP13A2 (SPG78), DYNC1H1, and BICD2 using a next generation sequencing-based technique. A copy number variation (CNV) test for SPAST, SPG7, and SPG11 was also performed. Twenty-three patients from 19 families (29.2%) had conclusive genetic findings, including 75.0% of families with autosomal dominant and 25.0% with autosomal recessive inheritance, and 15.7% of sporadic cases. Twelve families had mutations in the SPAST gene, usually with a pure HSP phenotype. Three sporadic patients had conclusive findings in the SPG11 gene. Two unrelated patients carried a homozygous pathogenic mutation c.233T>A (p.L78*) in SPG7 that is a founder Roma mutation. One patient had a heterozygous de novo variant in the KIF5A gene, and one had a compound heterozygous mutation in the ZYFVE26 gene. The combined genetic yield of our gene panel and CNV analysis for HSP was around 30%. Our findings broaden the knowledge on the genetic epidemiology of HSP, with implications for molecular diagnostics in this region.