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Whole Genome Sequencing Helps to Redefine a Rare Syndrome Associated with Neoteny

October 5, 2017

In 2009, there was a report about 16-year-old girl who seemed to be "frozen in time." She was almost the size of an infant, with the mental capacity of a toddler rather than a teenager. In addition, she suffered extreme developmental delay associated with multiple organ system dysfunctions. Her pediatrician felt that the girl’s condition had a genetic basis. However, in karyotyping and array chromosome genomic hybridization analysis, this girl appeared to have the genome of a normal female. At that time, there were no published reports on similar conditions.

Recently a group of scientists led by Dr. Brock Peters of Complete Genomics were able to perform whole genome sequencing (WGS) on six patients who had similar congenital anomalies and displayed neoteny. At last this rare disease was given a name, neotenic complex syndrome (NCS), which is consistent with medical conditions. This work was published in Genetics in Medicine on September 21, 2017.

In the study, scientists at Complete Genomics identified coding de novo mutations (DNMs) in five genes from five of the six patients. These genes fell into similar functional categories of transcription regulation and chromatin modification, and they are highly intolerant of variation in the human genome.

They also found inherited rare and family-specific single nucleotide variants in highly constrained genes in each family and found an excess of these variants (less than or equal to 0.001 MAF) in genes associated with intellectual disability and developmental delay (ID/DD) and autism spectrum disorder (ASD), compared to control samples. It was suggested that neotenic complex syndrome or NGS could result from multiple overlapping genetic diseases caused by inherited or de novo variations. In addition, noncoding de novo and inherited variations identified in this study could also contribute to this syndrome, although effects of these variations are currently beyond scientific understanding.

So far, NCS was only identified in females, and Complete Genomics scientists suggested two possibilities. First is that two of the five genes (DDX3X and HDAC8) bearing de novo mutations (DNMs) are located on the X chromosome, and they have high constraint scores, making it likely that loss of the single copy in males is lethal. Another possibility is that while certain neotenous traits, such as curiosity and plasticity of behavior, are shared equally between the sexes, human females are more pedomorphic in physical appearance than males. Thus, there may be a genetic tendency towards neoteny in females, which is amplified through mutation in these patients.

Due to the small sample size of this study, no definitive conclusion about the cause of this rare disease can be made at this point. However, this work has drawn considerable attention from the media and the public, and the hope is that in the near future, more people with similar disease will be willing to join the study.

According to NIH report, there are about 7,000 rare diseases in the world, and in the United States, an estimated 25 to 30 million people are living with rare diseases. Although researchers have made progress in learning about rare diseases, there is still much to do. As our understanding and knowledge grow, cures won’t be far behind.