title: Megalencephalic leukoencephalopathy with cysts in twelve Egyptian patients: novel mutations in MLC1 and HEPACAM and a founder effect.
abstract: Two genes causing megalencephalic leukoencephalopathy with subcortical cysts (MLC) have been discovered so far. Here, we identified MLC1 and HEPACAM mutations in ten and two patients, respectively. The molecular results included an unreported inframe duplication mutation (c.929_930dupCTGCTG; p.L309dup) of MLC1 and a novel missense mutation c.293G>A (p.R98H) of HEPACAM. Further, the previously reported missense (c.278C>T; p.S93L) and the deletion/insertion (c.908_918delinsGCA; p.V303Gfs*96) were found in one and 8 patients (75 %), respectively. The 8 patients carrying the p.V303Gfs*96 shared a similar haplotype suggesting a founder effect. All mutations were in the homozygous state proving the autosomal recessive mode of inheritance. The core phenotype of macrocephaly, subcortical cysts and white matter appeared homogeneous although the patients differed in the onset, clinical course, disease severity and brain imaging findings. Our study expands the spectrum of mutations in MLC1 and HEPACAM and supports the genetic and clinical heterogeneity. Further, It confirms c.908_918delinsGCA (p.V303Gfs*96) as a founder mutation among Egyptian patients. This finding will contribute to provide targeted testing for this mutation in MLC patients in our population.
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Tahrir street, Dokki, Cairo, Egypt. ghada.abdelsalam@yahoo.com.|Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt. ghada.abdelsalam@yahoo.com.
authors.forename: Ghada M H
authors.initials: GM
authors.lastname: Abdel-Salam
authors.affiliation: Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.|Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Hamid
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Tahrir street, Dokki, Cairo, Egypt.|Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Samira I
authors.initials: SI
authors.lastname: Ismail
authors.affiliation: National Institute of Neuromotor system, Cairo, Egypt.
authors.forename: Heba
authors.initials: H
authors.lastname: Hosny
authors.affiliation: Department of Pediatrics, Alexandria University, Alexandria, Egypt.
authors.forename: Tarek
authors.initials: T
authors.lastname: Omar
authors.affiliation: Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.|Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: Laila
authors.initials: L
authors.lastname: Effat
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Tahrir street, Dokki, Cairo, Egypt.|Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Mona S
authors.initials: MS
authors.lastname: Aglan
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Tahrir street, Dokki, Cairo, Egypt.|Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Samia A
authors.initials: SA
authors.lastname: Temtamy
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Tahrir street, Dokki, Cairo, Egypt.|Centre of Excellence for Human Genetics, National Research Centre, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
mesh_terms: D000293:Adolescent; D001921:Brain / Q000000981:diagnostic imaging; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003560:Cysts / Q000000981:diagnostic imaging* / Q000235:genetics*; D004534:Egypt; D005260:Female; D018703:Founder Effect; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000000981:diagnostic imaging* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; C487620:HEPACAM protein, human; C425069:MLC1 protein, human; D008565:Membrane Proteins; D011506:Proteins
keywords: Founder effect; HEPACAM; Intrafamilial variability; Leukoencephalopathy; MLC1; Megalencephaly; Portwine facial hemangioma with facial hemihypertrophy; Subcortical cysts