Low‐prevalence mosaicism of chromosome 18q distal deletion identified by exome‐based copy number profiling in a child with cerebral hypomyelination

Partial deletions of chromosome 18q distal lead to diverse congenital dysmorphic features such as hypomyelination short stature cleft lip and palate foot deformity and aural atresia. In contrast mosaicism of 18q distal deletion is a rarer situation with a highly variable phenotype, leading to clinical diagnostic challenges A Japanese female was born at term with no asphyxia. Her family history was unremarkable. At 5 months of age, the patient was admitted due to no head control. Physical examination revealed general muscle hypotonus, course face with hypertelorism, microcephaly (37.5 cm, −2.7SD), curly hair, lymphedema foot, short fifth fingers, and malposition of the first and the fifth foot digits. Gastrointestinal and urological examination revealed tubular anal duplication, right hydronephrosis, and vesicoureteral reflux. She subsequently presented focal epilepsy with the dominancy in the left upper limb and bilateral sensorineural hearing loss. Brain magnetic resonance imaging at 5 years of age showed complete agenesis of the corpus callosum (ACC) (Figure 1A) and diffuse cerebral hypomyelination (Figure 1B). At 10 years, she could sit supported, but say no words. G-banded analysis at 2 years of age showed a normal female karyotype (46,XX). We performed whole exome sequencing (WES) at 11 years of age. We could not find any possible pathogenic single nucleotide variants but found about 20 Mb deletion at 18q21.31-qter (chr18:56585841-77513763) by two copy number variants (CNVs) detection tools (Figure 1C,D). The quantitative polymerase chain reaction showed 0.8 of relative copy number ratio to a control sample. The FISH analysis using 18q unique probe showed two copy signal patterns in all the 10 lymphocytes prepared at 2 and 7 years. Finally, we evaluated the WES data by H3M2 program, a detection program of runs of homozygosity. In the normal two copy region, B allele frequency (BAF), the ratio between B-allele read counts and the total number of reads mapped to that position (A + B allele), showed three lines. Value of zero and 1.0 means homoor hemizygous for A and B alleles, respectively, and about 0.5 means heterozygous allele. However, in the deletion interval, BAF showed four lines, suggesting that two types of heterozygous alleles (mosaic A or B allele deletion in the A/B heterozygous allele) were present in this region (Figure 1D). Chromosomal microarray analysis (CytoScan HD Array, Affymetrix) showed arr[hg19] 18q21.2q23(51392374-78 014 123)x1-2 (Figure S1). Therefore, we concluded that this patient has the low-prevalence mosaic deletion of 18q21.2qter. The partial deletion on the chromosome 18q23 including myelin basic protein (MBP) and a galanin receptor (GALR1) is critically related to cerebral hypomyelination. Prior cohort studies reported that partial chromosome 18q deletion was identified in three of 26 patients with hypomyelination leukodystrophy, and none of 162 patients with ACC. Although the combination of cerebral hypomyelination and ACC is observed in several congenital diseases including pontocerebellar hypoplasia type 9 (caused by variants in AMPD2), glycine encephalopathy Received: 6 February 2019 Revised: 24 June 2019 Accepted: 13 July 2019 DOI: 10.1111/cga.12351