Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

Haemoglobinopathies including the thalassemias and sickle cell disease are known to be prevalent inherited disorders in most Arab countries with varying prevalence rates and molecular characterisation. β-thalassemia is encountered in polymorphic frequencies in almost all Arab countries with carrier rates of 1-11 % and a varying number of mutations. The most widespread mutation in Lebanon, Egypt, Syria, Jordan, Tunisia and Algeria is the IVS-I-110 (G>A). In the Eastern Arabian Peninsula, the Asian Indian mutations (IVS-I-5 (G>C), codons 8/9 (+G) and IVS-I (−25 bp del)) are more common. The α-thalassemias are encountered in the majority of Arab countries in frequencies ranging from 1 to 58 % with the highest frequencies reported from Gulf countries. The (−α 3.7 ) mutation is the most frequent followed by the non-deletional α2 polyadenylation signal mutation (AATAAA>AATAAG) and the α2 IVS1 5-bp deletion. The rates of sickle cell trait in Arab countries range from 0.3 to 30 %, with the Benin, the Arab-Indian and the Bantu haplotypes constituting the bulk of the haplotypes, leading to two major phenotypes; a mild one associated with the Arab-Indian and a severe one with the Benin and Bantu haplotypes. Public health approaches targeting prevention of haemoglobinopathies in Arab countries include newborn screening for sickle cell disease, and premarital screening for carriers of β-thalassemia and sickle cell disease. These services are still patchy and inadequate in many Arab countries recommending the upgrade of these services with strengthening of the education and training of health care providers and raising public awareness on the feasibility of prevention and care for haemoglobinopathies.

Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes.

Objectives:To assess the health related quality of life (HRQoL) in Iraqi Kurd children and adolescents with thalassemia, and identify the factors that affect it.Methods:In the period between May and June 2018, 100 thalassemic patients and 100 healthy subjects between the ages of 6-18 years were enrolled. The patients included 73 with thalassemia major (TM) and 27 with intermedia (TI). Patients were clinically re-evaluated, and the pediatric quality of life inventory (PedsQL) 4.0 was administered by both child and parent reports.Results:The mean HRQoL score of thalassemic patients was significantly lower than that of healthy subjects, with lowest scores in physical functioning. Furthermore, the mean HRQoL of TM was significantly lower than that of TI subgroup. Significantly lower mean HRQoL scores were seen in those taking ≥6 transfusions/year, with hepatitis C infection, with illiterate parents, and those on oral iron chelation. Pearson correlation revealed that HRQoL was negatively associated with age, frequency of transfusions, and serum ferritin, but positively correlated with age at starting transfusion and age at diagnosis. Only age and serum ferritin remained significant by multivariate analysis.Conclusion:This study shows that among Iraqi Kurds with thalassemia, the disease has a significant negative impact on quality of life, with age and serum ferritin being identified as independent predictors. Psychosocial, educational, and patient-centered management programs may be needed to improve HRQoL in this disease.

beta-Thalassemia (thal) is an important health problem in the Dohuk region of northern Iraq because of its high carrier rate and the frequency of consanguineous marriages. Thus, the need to establish an effective preventative program is paramount. As part of this effort, we initiated this study to determine the molecular basis of this disorder in the region. For the latter purpose, either parent of 104 registered beta-thal major/intermedia patients had their full blood counts, hemoglobin (Hb) electrophoresis, Hb A2 and Hb F quantitation performed. Their DNA was extracted, amplified and reverse hybridized to specific oligonucleotide probes to detect 20 beta-thal mutations. The testing detected 12 beta-thalassemic mutations. The eight most frequent were: IVS-II-1 (G-->A), codon 44 (-C), codon 5 (-CT), IVS-I-1 (G-->A), codon 39 (C-->T), IVS-I-6 (T-->C), codons 8/9 (+G) and IVS-I-5 (G-->C). These mutations accounted for 81.7% of the thalassemic defects in the studied individuals. The less frequent mutations were: codon 8 (-AA), IVS-I-110 (G-->A), codon 30 (G-->C) and codon 22 (-7 bp), and the beta-thalassemic defects remained uncharacterized in 11.5% of cases. This is the first study of beta-thal mutations from Iraq, and shows a frequency of thalassemic defects different from those reported in surrounding countries. It provides a foundation for prenatal genetic testing that will be part of a thalassemia prevention program in the Dohuk region.