Alpha-thalassemia X-linked intellectual disability syndrome identified by whole exome sequencing in two boys with white matter changes and developmental retardation.
Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is a genetic syndrome caused by mutation of the ATRX gene associated with chromatin remodeling. Recently, a wide spectrum of brain MRI abnormalities and clinical manifestations has been recognized. We describe two male patients with genetically confirmed ATRX syndrome, both presented with developmental delay and white matter changes without typical clinical characteristics of ATRX. Whole-exome sequencing revealed the presence of ATRX mutations: a novel c.6472A>G mutation in Case 1 and a previously reported c.6532C>T mutation in Case 2. These two cases expanded the genetic and clinical spectrum of ATRX syndrome, including brain MRI abnormalities. Our results suggest that male patients with developmental delay and widespread white matter changes, even without distinctive facial dysmorphism and hematologic abnormalities, should be suspected as ATRX syndrome. We support the clinical utility of whole-exome sequencing, particularly in ultra-rare neurological diseases with nonspecific developmental disabilities and atypical presentation.
Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jin Sook
JS
Lee
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Sangmoon
S
Lee
Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Byung Chan
BC
Lim
Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Ki Joong
KJ
Kim
Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Yong Seung
YS
Hwang
Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: murimchoi@snu.ac.kr.
Murim
M
Choi
Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: chaeped1@snu.ac.kr.
Jong-Hee
JH
Chae
D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics*; D059472:Exome; D006801:Humans; D007223:Infant; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D000075924:X-linked Nuclear Protein; D017085:alpha-Thalassemia / Q000235:genetics* / Q000473:pathology
D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
ATRX; Alpha-thalassemia X-linked intellectual disability syndrome; White matter changes; Whole-exome sequencing