Expanding the Genotype and Phenotype of SETD5-Related Neurodevelopmental Syndrome

Su(var)3-9, Enhancer of Zeste, and Trithorax Domain Containing 5 (SETD5) gene, located on chromosome 3q3.25, has 49 exons and codes a 1442-amino acid protein belonging to the SET methyltransferase family. 1 Fang Y. Zhang R. Wang Y. Cao L. Zhang Y. Cai C. A novel mutation in a common pathogenic gene (SETD5) associated with intellectual disability: a case report. Exp Ther Med. 2019; 18: 3737-3740 PubMed Google Scholar This protein catalyzes methylation of histone H3 and H4 lysine residues. 2 Martin C. Zhang Y. The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 2005; 6: 838-849 Crossref PubMed Scopus (1626) Google Scholar Pathogenic variants in SETD5 are known to result in intellectual disability. 3 Grozeva D. Carss K. Spasic-Boskovic O. et al. De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am J Hum Genet. 2014; 94: 618-624 Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar ,4 Kuechler A. Zink A. Wieland T. et al. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Eur J Hum Genet. 2015; 23: 753-760 Crossref PubMed Scopus (63) Google Scholar Other reported manifestations of SETD5-related neurodevelopmental syndrome include autism, stuttering, brachycephaly, low-set ears, synophrys, ptosis, depressed nasal bridge, thin upper lip, micrognathia, postaxial polydactyly, leg-length discrepancy, feeding difficulties, congenital heart defects, skeletal issues, gastrointestinal and genitourinary malformations, and behavioral difficulties. 3 Grozeva D. Carss K. Spasic-Boskovic O. et al. De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am J Hum Genet. 2014; 94: 618-624 Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar ,4 Kuechler A. Zink A. Wieland T. et al. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Eur J Hum Genet. 2015; 23: 753-760 Crossref PubMed Scopus (63) Google Scholar We hereby describe a patient with a novel variant and hitherto unknown manifestations of SETD5-related neurodevelopmental syndrome. We extracted information from our patient's chart after our Institutional Review Board granted approval. A two-year-old female with microcephaly, coarse facial features, everted lateral canthi, and failure to thrive was admitted to our institution with hypothermia and bradypnea. The family did not report consanguinity. She was hyporeflexic but not weak. Magnetic Resonance Imaging of the brain showed nonspecific periventricular white matter hyperintensities. She was noted to have pigmentary retinopathy and central hypothyroidism requiring levothyroxine supplementation. She gained weight in hospital and was determined to have calorie-deprivation-related malnutrition. Development improved partially with levothyroxine. Electrodiagnostic studies did not reveal any abnormalities. Subsequently, next-generation sequencing revealed a novel pathogenic heterozygous variant (c.896_897del [p.Ile299Argfs∗13]). This change creates a premature translational stop signal in the SETD5 gene and is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETD5 are considered pathogenic. 3 Grozeva D. Carss K. Spasic-Boskovic O. et al. De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability. Am J Hum Genet. 2014; 94: 618-624 Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar ,4 Kuechler A. Zink A. Wieland T. et al. Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Eur J Hum Genet. 2015; 23: 753-760 Crossref PubMed Scopus (63) Google Scholar A homozygous variant in GALC gene was deemed benign. No variants of unknown significance possibly accounting for an additional and unrelated genetic disorder were reported. Pigmentary retinopathy and central hypothyroidism have not been reported with this condition previously. It has been shown in mouse model that SETD5 gene regulates retinal endothelial cell survival 5 Villain G. Poissonnier L. Noueihed B. et al. miR-126-5p promotes retinal endothelial cell survival through SetD5 regulation in neurons. Development. 2018; 145dev156232 PubMed Google Scholar ; this may explain pigmentary retinopathy in our patient. Moreover, moyamoya angiopathy has been reported with SETD5 variants. 6 Pinard A. Guey S. Guo D. et al. The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. Genet Med. 2020; 22: 427-431 Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar We are not able to explain the pathogenesis of central hypothyroidism based on available literature. Our patient expands the genotype and phenotype of SETD5-related neurodevelopmental syndrome with the caveat that we are not able to definitively rule out the possibility of these two phenotypic manifestations being unrelated to SETD5.