OBJECTIVE: To explore the clinical characteristics and genetic basis of two brothers featuring X-linked alpha thalassemia mental retardation (ATR-X) syndrome. METHODS: An infant who had presented at the Qilu Children's Hospital in 2020 for unstable upright head and inability to roll over and his family were selected as the study subjects. The clinical features of the child and one of his brothers were summarized, and their genomic DNA was subjected to targeted capture and next generation sequencing (NGS). RESULTS: The brothers had presented with mental retardation and facial dysmorphisms. NGS revealed that they had both harbored a hemizygous c.5275C>A variant of the ATRX gene located on the X chromosome, which was inherited from their mother. CONCLUSION The siblings were diagnosed with ATR-X syndrome. The discovery of the c.5275C>A variant has enriched the mutational spectrum of the ATRX gene.
Humans ; Infant ; Male ; alpha-Thalassemia/diagnosis* ; Ataxia Telangiectasia Mutated Proteins/genetics* ; East Asian People ; Intellectual Disability/genetics* ; Mental Retardation, X-Linked/diagnosis* ; Pedigree ; X-linked Nuclear Protein/genetics*

Mutation of the ATRX gene leads to X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome and several other X-linked mental retardation syndromes. We report the first case of ATR-X syndrome documented here in Korea. A 32-month-old boy came in with irritability and fever. He showed dysmorphic features, mental retardation and epilepsy, so ATR-X syndrome was considered. Hemoglobin H inclusions in red blood cells supported the diagnosis and genetic studies confirmed it. Mutation analysis for our patient showed a point mutation of thymine to cytosine on the 9th exon in the ATRX gene, indicating that Trp(C), the 220th amino acid, was replaced by Ser(R). Furthermore, we investigated the same mutation in family members, and his mother and two sisters were found to be carriers.
Amino Acid Substitution ; Body Dysmorphic Disorders/complications ; Child, Preschool ; DNA Mutational Analysis ; Epilepsy/complications ; Exons ; Hemoglobin H/*genetics ; Humans ; Male ; Mental Retardation/complications ; Mental Retardation, X-Linked/complications/diagnosis/genetics ; Point Mutation ; Republic of Korea ; alpha-Thalassemia/complications/diagnosis/genetics

OBJECTIVETo investigate whether the four boys with delayed motor development and intellectual disability suffer from MECP 2 duplication syndrome.

METHODBlood specimens and clinical data of four patients and mothers of patient 2 and patient 4 were collected. Genomic DNA was extracted from peripheral blood using DNA extraction kit. At first multiplex ligation-dependent probe amplification (MLPA) was employed in 4 patients, two distinct kits SALSA P036 and P070 for sub-telomere screening, and SALSA P245 for the 22 common microdeletion and microduplication syndromes. Then array-CGH analysis was carried out. Two mothers of patients were tested by array- comparative genomic hybridization (CGH) and X chromosome inactivation analysis.

RESULTAll the 4 patients presented with severe hypotonia, delayed motor development, intellectual disability and absent or limited language. Three patients manifested recurrent pneumonia in infancy except patient 2. Four patients had duplication on chromosome Xq28 with MLPA kit SALSA P245. Array-CGH identified the size of each duplication on Xq28. The precise size of each duplication was different in the four patients: patient 1, 14.931 Mb, patient 2, 0.393 Mb, patient 3, 0.482 Mb and patient 4, 0.299 Mb. To compare Xq28 duplications with UCSC database (http://genome.ucsc.edu/) revealed that each duplication harbors the MECP 2 and HCFC 1 gene. Mothers of patient 2 and patient 4 also carried microduplication on Xq28. X chromosome inactivation analysis demonstrated completely skewed inactivation (0: 100) and it is the inactive allele that passed on to the patients.

CONCLUSIONFor patients that present with delayed motor development, intellectual disability, hypotonia, absent or limited language and recurrent infection, combination of MLPA and array- CGH is effective and specific diagnostic methods of MECP 2 duplication syndrome.

Chromosomes, Human, X ; genetics ; Comparative Genomic Hybridization ; Gene Duplication ; Humans ; Male ; Mental Retardation, X-Linked ; diagnosis ; genetics ; Methyl-CpG-Binding Protein 2 ; genetics ; Multiplex Polymerase Chain Reaction ; X Chromosome Inactivation