Clinical and genetic analysis of a rare syndrome associated with neoteny

Purpose We describe a novel syndrome in seven female patients with extreme developmental delay and neoteny. Methods All patients in this study were female, aged 4 to 23 years, were well below the fifth percentile in height and weight, had failed to develop sexually, and lacked the use of language. Karyotype and array chromosome genomic hybridization analysis failed to identify large-scale structural variations. To further understand the underlying cause of disease in these patients, whole-genome sequencing was performed. Results In five patients, coding de novo mutations (DNMs) were found in five different genes. These genes fell into similar functional categories of transcription regulation and chromatin modification. Comparison to a control population suggested that individuals with neotenic complex syndrome (NCS)—a name that we propose herein—could have an excess of rare inherited variants in genes associated with developmental delay and autism, although the difference was not significant. Conclusion We describe an extreme form of developmental delay, with the defining characteristic of neoteny. In most patients we identified coding DNMs in a set of genes intolerant of haploinsufficiency; however, it is not clear whether these contributed to NCS. Rare inherited variants may also be associated with NCS, but more samples need to be analyzed to achieve statistical significance.