Prevalent MLC1 mutation causing autosomal recessive megalencephalic leukoencephalopathy in consanguineous Palestinian families.

BACKGROUND: Recessive forms of megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) is a rare early-onset leukodystrophy that presents with macrocephaly, seizures, slowly progressive gross motor deterioration, and MRI evidence of diffuse symmetric white matter swelling and subcortical cysts in the anterior temporal and frontoparietal regions. Later in the disease course, significant spasticity and ataxia develop, which may be accompanied by intellectual deterioration. This disease is caused mostly by biallelic pathogenic variants in the MLC1 gene. METHODS: In this study, we analysed the clinical and molecular architecture of 6 individuals, belonging to 4 unrelated consanguineous Palestinian families, presenting with consistent MLC features. We sequenced the entire coding and flanking intronic regions of the MLC1 gene. RESULTS: In all recruited individuals, we detected one recurrent homozygous splice donor mutation NM_015166.4: c.423 + 1G > A. All parents were heterozygous carriers. The mutation abolishes a highly conserved splice site in humans and other species. In silico splice predictors suggested the loss of a canonical splice donor site (CADD score 33.0. SpliceAI: 0.980). The c.423 + 1G > A variant is rare; it was detected in only 4 heterozygous carriers in gnomAD. CONCLUSION: In this study, we identified a recurrent MLC1 variant (c.423 + 1G > A) as the cause of MLC among a group of Palestinian patients originating from a particular region of the country. Cost-effective studies should be performed to evaluate the implementation of carrier screening in adults originating from this region. Our findings have the potential to contribute to improved genetic diagnosis and carrier testing for individuals within this population and the wider community.

Homozygous frameshift variant in NTNG2, encoding a synaptic cell adhesion molecule, in individuals with developmental delay, hypotonia, and autistic features.

Regulation of neuronal connectivity and synaptic communication are key to proper functioning of the brain. The Netrin-G subfamily and their cognate receptors are vertebrate-specific synaptic cell adhesion molecules with a role in synapse establishment and function, which seem to have co-evolved to contribute to higher brain functions. We identified a homozygous frameshift variant in NTNG2 (NM_032536.3: c.376dup), encoding Netrin-G2, in eight individuals from four families with global developmental delay, hypotonia, secondary microcephaly, and autistic features. Comparison of haplotypes established this as a founder variant. Previous studies showed that Ntng2-knockout mice have impaired visual, auditory, and motor coordination abilities required for demanding tasks, as well as possible spatial learning and memory deficits. Knockout of Ntng2 in a cellular model resulted in short neurites, and knockout of its trans-synaptic partner Ngl2/Lrrc4 in mice revealed autistic-like behavior and reduced NMDAR synaptic plasticity. The Ngl2/Lrrc4-knockout mouse phenotype was rescued by NMDAR activation, suggesting a mechanistic link to autism spectrum disorder. We thus propose NTNG2 as a candidate disease gene and provide further support for the involvement of Netrin-G2 in neuropsychiatric phenotypes.

Factors associated with continuing emergence of ß-thalassemia major despite prenatal testing: a cross-sectional survey.

PURPOSE: Health care initiatives focusing on prenatal testing and premarital genetic screening aiming to reduce the incidence of ß-thalassemia have emerged during the last decade. In Palestine, 4% of the population are known thalassemia carriers with new cases continuing to appear despite the availability of prenatal testing. This study aims to identify factors that influence the decision to retain or abort fetuses affected by ß-thalassemia in Palestine. METHODS: Convenience sampling was used to select 32 women (72 fetuses) who were at risk of having a baby with ß-thalassemia. A questionnaire on prenatal testing, test results, pregnancy outcomes, and factors influencing the decision to terminate the pregnancy were used for this cross-sectional study. The data were analyzed using SPSS version 17. RESULTS: Among the fetuses screened, 36 (50%) were thalassemia carriers and 20 (28%) had ß-thalassemia; 17 (85%) affected fetuses were aborted. Religious beliefs were the most cited reason for opposing abortion while prior experience with ß-thalassemia patients and awareness programs promoted abortions. Mothers who opted to retain an affected fetus had modest educational attainment. Higher educational level was significantly associated with the decision to abort an affected fetus (p<0.05). CONCLUSION: A religious consensus is needed on the abortion of fetuses affected by ß-thalassemia. Improving female education and increasing awareness on thalassemia could help reduce the incidence of ß-thalassemia in Palestine and around the world.

Incidence of cleft lip and palate in the palestinian territories: a retrospective study from the Makassed Hospital neonatal unit.

BACKGROUND: Cleft lip, with or without cleft palate (CL±P), is the most common craniofacial anomaly in newborns. The incidence of CL±P varies among different ethnic populations and is presumed to be higher in developing countries. In the Middle East, the incidence has variably been reported as 0.3 to 2.19 per 1000 live births and is generally regarded as similar to Caucasians. There is currently no literature reporting the incidence of clefting in Palestinians living in the territories. Reports from Palestinian populations in Israel and Jordan infer an incidence of 1.39 per 1000 live births. However, the reported incidence in stable populations may not reflect the actual incidence of clefting in the territories. METHODS: This is a retrospective study examining all newborn records at Makassed Maternity Hospital in Jerusalem between January 1, 1986, and December 12, 1995. Data were collected by the senior author (A.D.) and interpreted by coauthors. Frequencies were established based on the number of isolated and nonisolated CL±P born during this time period. RESULTS: During the 10-year period from January 1, 1986, to December 12, 1995, there were 33,239 live births. Among these births, there were 35 isolated and nonisolated combined CL±P born (1.05/1000 live births). CONCLUSIONS: Based on this limited data set from a single, tertiary referral hospital, we conclude that the prevalence rate of CL±P among a Palestinian population may be less than that reported in surrounding areas. However, more broadly based studies using nationalized birth registries are required to determine an accurate prevalence rate of CL±P among Palestinians.

Prevalence of patients with end-stage renal disease on dialysis in the West Bank, Palestine.

This study was conducted to determine the point prevalence of patients with end-stage renal disease (ESRD) on dialysis in the West Bank, Palestine. As part of this study, the following parameters were studied: District, gender, age and presumed cause. This cross-sectional study was undertaken during the period 26-30 December 2010 at all dialysis units in the West Bank, and included all cases of ESRD on dialysis. The total prevalence of patients with ESRD on dialysis during the study period was 240.3 per million population (PMP). The highest prevalence was seen in Jericho city. There were 57.7% males and 42.4% females in the study. The majority of patients (62.3%) were living in villages, while 28.8% were living in cities and 8.9% were living in refugee camps. Most of the patients (45%) were aged between 45 and 64 years. The vast majority of patients were either diabetic (22.5%) or hypertensive (11.1%) or both at the same time (10.6%). There were a considerable number of patients in whom the cause was undetermined (27.6%). The majority of recorded cases of congenital causes were from the Hebron, Jenin and Tubas districts. The prevalence of ESRD noted in our study is comparable with other regional countries but far below the rate recorded in industrialized countries. In the Palestinian territories, there is a general lack of national statistics and surveys, particularly in the public health section. Increased efforts and awareness should be focused on the prevention and treatment of diabetes mellitus and hypertension as they are the main causes of ESRD. There should also be an additional enhancement and implementation of strategies for the registration of data in order to conduct periodic comparisons and analytical studies to improve the management and quality of life of ESRD patients.