| 제목 |
Clinical characteristics of 14q11.2 microdeletion in Korean children with developmental delay |
| 소속 |
CHA Bundang Medical Center, Department of Rehabilitation Medicine1, Fertility Center, CHA Gangnam Medical Center, Genetics Laboratory2 |
| 저자 |
Kye Hee Cho1*, Joonhyun Park1, Sung Han Shim2, MinYoung Kim1† |
Introduction
Multiplex ligation-dependent probe amplification (MLPA) assay is considered as the gold standard for detection of copy number variations including microdeletions/duplications. However, accurate detection using MLPA is technically challenging due to restricted number of DNA probes that can be examined among multiple genomic regions, and the high cost of chip-based assays. In 49 children with developmental delay/ intellectual disability who had normal MPLA results between 2011 and 2016, microarray-based Comparative Genomic Hybridization (aCGH) was applied. As results, cytogenetic aberrations were identified in 35 patients including eight patients with microdeletion at 14q11.2. Four patients had a single microdeletion at 14q11.2, whereas the other four had combined cytogenetic abnormalities. The common region of microdeletion between 225,337,51 and 229,593,62 bp did not overlap with the previously reported critical region of 14q11.2 deletion between 20,896,740 bp and 20,931,826bp from Canadian aCGH study of children with developmental delay. The common features in Korean children are described for the specific loci of 14q11.2 microdeletion.
Clinical Manifestations
All patients had intellectual disability mostly in profound degree and growth retardation: height was between 25% and 50% in four patients, 10% and 25% in one, less than 3% in two at ages older than three. Most patients, except patient 4, were born at full term. Patient 5 had received growth hormone replacement therapy for short stature; however, weighted 25kg at 23 years due to poor oral intake. Common features in children with a single 14q11.2 deletion include autism, profound intellectual disability with relatively mild motor dysfunction. Those with additional cytogenetic aberrations tend to be severer motor dysfunction that most cannot walk (Table 1).
Discussion
The loci of the microdeletion in most patients were in close vicinity and similar in size between 42kb to 60kb. The region of microdeletion shared in most patients contains 10 RefSeq genes (Fig.1, Table 2) including nuclear genes encoding mitochondrial components, OXA1L and MRPL52. OXA1L codes mitochondrial inner membrane insertase that interact with both mitochondrial inner membrane and mitoribosome. MRPL52 codes mitochondrial ribosomal protein L52, a component of a mitoribosome large subunit. Oxidative phosphorylation essential for ATP production takes place in the mitochondrial inner membrane. The defects of genes encoding mitochondrial proteins are particularly interesting as the association of mitochondrial dysfunction and autism has been introduced. Only a few mutations of mitoribosome proteins have been identified for protein synthesis machinery. The translation of proteins to the mitochondrial inner membrane is an important part of oxidative phosphorylation that abnormal translation may be related to the clinical features of 14q11.2 deletion.
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GA, gestational age; BW, birth weight; Wt, weight in percentile; HC, head circumference; GMFCS, Gross Motor Function Classification Systems; abn, abnormal; bMRI, brain MRI; EEG, electroencephalography; NA, not available; m, on antiepileptic drugs; Underlined number patients have 14q11.2 microdeletion only. GMFCS levels and IQ were scored at ages over five years. IQ scores are based on Munich Functional Developmental Diagnostics unless otherwise stated. Spasticity is based on modified Ashworth scales (MAS): + = grade ≤ 1+, ++= grade ≥2 *based on Korean Wechsler Preschool and Primary Scale of Intelligence-IV †based on Korean Wechsler Adult Intelligence Scale-IV
Figure. Loci of microdeletion at 14q11.2. Patients in blue color had combined genetic aberrations whereas patients in red had a single microdeletion at 14q.11.2. The location of each gene within the common region of microdeletion are depicted in yellow column.
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