الفهرس 
Aim of the workOnly 14 pages are availabe for public view
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Abstract
Hydrocephalus (HC) is a significant medical condition, characterized by abnormalities in the flow or resorption of cerebrospinal fluid (CSF) resulting in ventricular dilatation. HC is classified into: congenital HC which presents at birth and is often associated with developmental defects, and acquired HC which occurs after development of the brain and ventricles, or according to site of obstruction into communicating or non-communicating hydrocephalus. HC can also be classified into syndromic and non-syndromic (isolated) depending on whether additional congenital anomalies are present or not. Isolated hydrocephalus can be inherited in autosomal recessive, autosomal dominant or X-linked recessive trait. X-linked hydrocephalus (OMIM# 307000), associated with stenosis of the aqueduct of sylvius (HSAS), is the most common heritable form of hydrocephalus in males. It occurs due to hemizygous mutations in L1CAM gene which is the most common gene associated with X-linked mode of inheritance.
This study aims to determine the contribution of L1CAM gene in Egyptian families with X-linked hydrocephalus, which will greatly improve our knowledge about the spectrum of different mutations in the L1CAM gene and further establish any correlation with phenotype.
This study included 25 male patients/fetuses, aged from few months to 13 years, with congenital isolated hydrocephalus. Patients were clinically diagnosed with X-linked hydrocephalus based on the detailed clinical evaluations (antenatal, perinatal, postnatal history), pedigree analysis and brain imaging studies (CT and/or MRI). Sanger sequencing of the whole coding region of the L1CAM gene revealed pathogenic variants in 8/25 patients (six patients and two fetuses), with detection rate of 32%. All variants were shown to be maternally inherited. The eight different hemizygous variants included 4 novel ones. The missense variant c.354T>A (p.Asn118Lys), with family history consistent to hydrocephalus; the framshift deletion variant c.1067_1076delTCCAGGGCAG (p.Val356GlyfsTer31), which was detected in 18 weeks fetus, whose mother had a history of pregnancy terminations due to hydrocephalus; the nonsense variant c.2556 C>A (p.Tyr852Ter), in which the patient showed the presence of Hirschsprung disease (HSCR), and the splice site variant c.3457+3A>G, that results in premature termination of protein translation. On the other hand, four previously reported variants were also detected. The pathogenic silent mutation c.645C>T (p.Gly215=) that alters splicing of the gene, the nonsense variant c.1097G>A (p.Trp366Ter), with no family history of hydrocephalus; the nonsense variant c.1672C>T (p.Arg558Ter) in a fetus whose parents have one healthy child, and the missense variant c.3581C>T (p.Ser1194Leu), that was the only reported mutation with Hereditary Spastic Paraplegia (HSP), the patient had many diseased siblings with hydrocephalus and HSP, with family history of two male infant deaths with congenital hydrocephalus.
The clinical manifestations of the patients are in line with those frequently observed including communicating hydrocephalus, and agenesis of corpus callosum. Moreover, rippled ventricles with subdural collection and asymmetry of ventricles after shunt operation were observed in one patient and two patients, respectively. In addition, abnormal basal ganglia was found in four patients that seems to be an additional distinct new finding. One patient with a novel nonsense variant was found to have Hirschsprung’s disease which is rarely associated with L1CAM-related hydrocephalus. This patient displayed additionally multiple porencephalic cysts and encephalomalacia secondary to hemorrhage due to repeated infection after shunt operation. Patients with the missense variants showed long survival while those with truncating variants showed poor prognosis.
In conclusion, this is the first study conducted on Egyptian patients to shed light on the clinical, brain imaging data and mutational spectrum of L1CAM-related hydrocephalus. The genetic screening of L1CAM gene identified four novel variants expanding the mutational spectrum of this disorder.
The molecular data obtained in this study enabled us to provide accurate genetic counseling, carrier detection of at-risk female relatives and prenatal diagnosis of families with L1CAM mutations.
On the other hand, Sanger sequencing of other known hydrocephalus genes or preferably the use of next generation sequencing is mandatory to reach the genetic cause of the 17 L1CAM negative patients described in this study.