Analyzing copy number variation in rare childhood disorders
The Center for Rare Childhood Disorders strives to diagnose and formulate a treatment plan for children with rare disorders. Patients with rare childhood disorders are likely to contain a disorder-inflicting copy number variant. Copy number variations (CNVs) occur when a large genomic region is deleted or multiplied. Analysis of CNVs in affected patients can lead to an increased diagnostic rate and a treatment plan to prolong lifespan. To analyze CNVs in rare childhood disorders, we sequenced the patient’s exome with next generation sequencing. Afterwards, an in-house developed pipeline, tCoNut, used the raw reads generated through exome sequencing to calculate the B allele frequency (BAF) and Log2 fold change based on single nucleotide changes and read depth. We checked over 50 families within our Center for Rare Childhood Disorders without a previous diagnosis, and verified CNVs with BAF plots, Log2 fold change, and the integrative genomic viewer (IGV). As an example, in family CRDC0162, we discovered a de novo deletion on chromosome 16p13.11p12.3 that could explain the child’s partial or full phenotype such as PANDAS, spina bifida occulta, borderline CSF folate deficiency, eczema, developmental delay, chronic sinusitis, sensory processing disorder, chronic constipation, cecostomy tube, ADHD, anxiety, and 2-3 toe syndactyly. The deleted region on chromosome 16 contains the NDE1 gene, which may be linked to the child’s disorder. In addition, microdeletions in this genomic area (16p13.11 microdeletion syndrome), probably due to the loss of NDE1, have also been associated previously with certain clinical features of our patient. We believe that the copy loss of the NDE1 gene in this child is responsible for either his partial or full phenotype. We hope to expand our diagnostic rate within the Center for Rare Childhood Disorders with CNV analysis, which could lead to improved clinical guidance, treatment, and patient care.