A De Novo Missense Variant in POU3F2 Identified in a Child with Global Developmental Delay

Abstract

Many genetic and nongenetic causes for developmental delay in childhood could be identified. Often, however, the molecular basis cannot be elucidated. As next-generation sequencing is becoming more frequently available in a diagnostic context, an increasing number of genetic variations are found as causative in children with developmental delay.

We performed trio exome sequencing in a girl with developmental delay and minor dysmorphological features. Using a filter for de novo variants, the heterozygous missense variant c.812A>T, p.(Glu217Val) was found in the candidate gene POU3F2 in our patient.

POU3F2 plays an important role in neuronal differentiation and hormonal regulation. To date, it has not been associated with monogenic disorders. Studies on Pou3f2 knockout mice highlighted the importance of this protein in the development of the brain. Furthermore, microdeletions with an overlapping region including only POU3F2 and FBXL4 were linked to developmental delay in six unrelated families. Therefore, POU3F2 is a strong candidate gene for developmental delay, although functional assays proving this assumption still have to be done.

Keywords

de novo - missense - POU3F2 - developmental delay - dysmorphological - exome sequencing

• References

• 1 McEvilly RJ, de Diaz MO, Schonemann MD, Hooshmand F, Rosenfeld MG. Transcriptional regulation of cortical neuron migration by POU domain factors. Science 2002; 295 (5559): 1528-1532
• 2 Andersen B, Rosenfeld MG. POU domain factors in the neuroendocrine system: lessons from developmental biology provide insights into human disease. Endocr Rev 2001; 22 (01) 2-35
• 3 Sturm RA, Herr W. The POU domain is a bipartite DNA-binding structure. Nature 1988; 336 (6199): 601-604
• 4 Kemler I, Schaffner W. Octamer transcription factors and the cell type-specificity of immunoglobulin gene expression. FASEB J 1990; 4 (05) 1444-1449
• 5 Hara Y, Rovescalli AC, Kim Y, Nirenberg M. Structure and evolution of four POU domain genes expressed in mouse brain. Proc Natl Acad Sci U S A 1992; 89 (08) 3280-3284
• 6 Nakai S, Kawano H, Yudate T. , et al. The POU domain transcription factor Brn-2 is required for the determination of specific neuronal lineages in the hypothalamus of the mouse. Genes Dev 1995; 9 (24) 3109-3121
• 7 Lujan E, Chanda S, Ahlenius H, Südhof TC, Wernig M. Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci U S A 2012; 109 (07) 2527-2532
• 8 Tian C, Li Y, Huang Y. , et al. Selective generation of dopaminergic precursors from mouse fibroblasts by direct lineage conversion. Sci Rep 2015; 5: 12622
• 9 Dominguez MH, Ayoub AE, Rakic P. POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex. Cereb Cortex 2013; 23 (11) 2632-2643
• 10 Kasher PR, Schertz KE, Thomas M. , et al. Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability. Am J Hum Genet 2016; 98 (02) 363-372
• 11 Nasu M, Yada S, Igarashi A. , et al. Mammalian-specific sequences in pou3f2 contribute to maternal behavior. Genome Biol Evol 2014; 6 (05) 1145-1156
• 12 Grantham R. Amino acid difference formula to help explain protein evolution. Science 1974; 185 (4154): 862-864
• 13 Verrijzer CP, Kal AJ, van der Vliet PC. The oct-1 homeo domain contacts only part of the octamer sequence and full oct-1 DNA-binding activity requires the POU-specific domain. Genes Dev 1990; 4 (11) 1964-1974
• 14 Deciphering Developmental Disorders S; Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 2017; 542 (7642): 433-438
• 15 Firth HV, Richards SM, Bevan AP. , et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using Ensembl resources. Am J Hum Genet 2009; 84 (04) 524-533