R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.
Division of Neurology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Kheng-Seang
KS
Lim
Division of Neurology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Ai-Huey
AH
Tan
Genetics and Molecular Biology Unit, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
Chun-Shen
CS
Lim
Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Kek-Heng
KH
Chua
Genetics and Molecular Biology Unit, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
Ping-Chin
PC
Lee
Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Norlisah
N
Ramli
Department of Medicine, Hospital Queen Elizabeth, Sabah, Malaysia.
Giri Shan
GS
Rajahram
Department of Radiology, Hospital Queen Elizabeth, Sabah, Malaysia.
Fatimah Tina
FT
Hussin
Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Kum-Thong
KT
Wong
Department of Pathology and Laboratory Medicine, UT Health Science Center, Houston, TX, United States of America.
Meenakshi B
MB
Bhattacharjee
Genetics and Molecular Biology Unit, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.
Ching-Ching
CC
Ng
D000328:Adult; D046589:CADASIL / Q000208:ethnology* / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D006801:Humans; D008296:Malaysia / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*
C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch