Xq26.3 duplication suspected as X-lag in a boy with motor delay and low muscle tone and no gigantism: The impact of high-resolution molecular cytogenetics

Abstract

Introduction: Genomic disorders result from loss or gain of DNA material. Copy number variants (CNVs) can be pathogenic if they involve a dosage-sensitive gene(s) or regulatory elements. We recently reported a genomic disorder caused by Xq26.3 duplications in patients with X-linked acrogigantism (X-LAG). The complexity of Xq26 rearrangements and their size can make them confusing for clinical counseling. Case Report: A 4-year-old male presented with developmental delay and low muscle tone. He was born at 39 weeks gestation and his birth weight was 3100g (>10th <25th centile). He has a family history of mild gross motor delay, with both mother and maternal uncle walking at 18 months. He was first noted to have motor delay at 6 months of age, sitting unaided at 10 months. He never crawled, and eventually walked at 32 months. He has delays in fine motor movements, and had no discernible speech, and delayed receptive language skills at 32 months. At age 4 he can now follow simple commands and communicate with some single words. On examination he has no dysmorphic features, and does not display features of gigantism or acromegaly. His height tracks along the 75thcentile in keeping with his mid-parental height, while his head circumference measures at the 50th centile. His weight tracks between the 5th and 10thcentiles for age. Investigations to date revealed normal pituitary function and biochemistry but clinical grade comparative genomic hybridization (CGH) reported that he may possibly carry an Xq26.3 chromosomal defect encompassing the X-LAG region. We, thus, performed high-density CGH (HD-aCGH) on leukocyte-derived DNA and detected an Xq26.3 duplication spanning about 650 kb. The duplicated region, inherited from the mother, encompasses several genes including 2 long non-coding RNAs (LINC00633 and SMIM10L2A), 2 transcription factors (ZNF75D and ZNF449), and cancer/testis antigens (CT55and the CT45 gene family). The region is flanked by numerous low copy repeats and the duplication is potentially mediated by nonallelic homologous recombination. A query of different databases of genomic variants (DECIPHER, dbVar, ClinVar) for patients with overlapping rearrangements of similar size and without other CNVs returned 13 entries. Several of these patients show common phenotypes, including intellectual disability and developmental delay. Interestingly, one case was reported with delayed gross motor development. Conclusions: The microduplication detected in this case does not overlap with the described X-LAG CNV region and is indeed associated with a different phenotype. Some of the duplicated genes were reported to regulate chondrogenesis and promote cell growth and thus warrant further investigation to determine their contribution to the phenotype. Low-resolution clinical grade CGH in cases with doubt should be followed by HD-aCGH before counseling the patients and their families.L6171513642017-07-10 <br />