ClinVar Genomic variation as it relates to human health

This approximately 9.1 Mb deletion was detected in a 10 year old male with a history of expressive language disorder, autism spectrum disorder, sleep difficulties, and ADHD. This deletion includes 25 genes, 4 of which have been associated with clinical disorders. Two genes, NEK1 and MSMO1, are associated with autosomal recessive conditions indicating the patient is a carrier for these conditions. Heterozygous missense variants in the TLL1 gene have been associated with atrial septal defects (Stanczak et al. 2009). A single missense variant in PALLD has been reported to increase susceptibility to pancreatic cancer. PALLD has conflicting literature regarding its link to pancreatic cancer risk, however. Some publications indicate a risk while other literature refutes this. Functionally, this variant has been shown to result in overexpression of the gene, and overexpression of the gene is not expected with a gene deletion (Pogue-Geile et al. 2006). Overlapping deletions have been reported in the literature in an individual with Robin sequence, mild developmental delays and ulnar anomalies and another individual with congenital heart defect, growth delay, and minor skeletal anomalies (Keeling et al. 2001; Xu et al. 2012). Overlapping deletions have been identified in several individuals in DECIPHER including an individual with a broad forehead, downslanted palpebral fissures, high anterior hairline, and intellectual disability (Case 257358). An overlapping variant was also submitted to ClinVar/dbVar in an individual with abnormal facial shape and learning disability (nsv532029). A follow-up echocardiogram for the patient was normal. Parental follow-up testing identified that this deletion is secondary to a maternal balanced rearrangement. Maternal family history includes a relative with multiple miscarriages, a pregnancy with congenital anomaly of the brain/skull, and a child with a congenital heart defect suggesting others in the family may also carry the balanced rearrangement.