Supplementary Material for: Short stature and response to growth hormone treatment in CUL3-related neurodevelopmental disorder

Introduction Recent research has expanded the spectrum of genetic causes for growth failures. Patients with CUL3-related neurodevelopmental disorder (NDD) present with variable phenotypic manifestations and growth retardation has been observed in some of these patients.
Case Presentation We present two families with NDD and variable degree of short stature. The proband in Family 1 had short stature (-3.0 SDS), developmental delay, learning difficulties and autism spectrum disorder. Whole exome sequencing (WES) revealed a novel likely pathogenic heterozygous nonsense CUL3 variant c.420C>G, p.Tyr140Ter. The variant was also identified in her non-identical twin sister, who presented with short stature and NDD, and in their father, who had NDD and epilepsy but normal height. The proband and her sister were treated with growth hormone (GH) with good response. The proband and his brother in Family 2 presented with short stature during childhood, NDD and facial dysmorphism. WES identified a heterozygous likely pathogenic nonsense CUL3 variant c.442C>T, p.Arg148Ter in the proband and his brother. The variant was inherited from their mother, who had facial dysmorphism and hypertension but normal height.
Conclusion CUL3-related NDD can be associated with growth retardation. We observed a good response to GH therapy in two of our patients with short stature. Our finding expands the spectrum of disease-causing variants in CUL3 and demonstrates variable intra-familial clinical expressivity.