A number sign (#) is used with this entry because of evidence that Heyn-Sproul-Jackson syndrome (HESJAS) is caused by heterozygous mutation in the DNMT3A gene (602769) on chromosome 2p23.

Heterozygous mutation in the DNMT3A gene can also cause Tatton-Brown-Rahman syndrome (TBRS; 615879), which is a reciprocal phenotype with macrocephaly, overgrowth, and impaired intellectual development.

Heyn-Sproul-Jackson syndrome (HESJAS) is characterized by microcephalic dwarfism and global developmental delay (Heyn et al., 2019).

Heyn et al. (2019) reported 3 unrelated patients, aged 13 years, 19 months, and 4.5 years, with microcephalic dwarfism and global developmental delay. All had intrauterine growth retardation and severely delayed postnatal growth. The patients had proportionate short stature (-3.2 to -5.4 SD), low weight (-2.6 to -5.2 SD), and microcephaly (-4.1 to -6.6 SD). Growth hormone levels were normal, and brain imaging, performed in 2 patients, was normal. One patient had 11 pairs of ribs, but skeletal surveys and bone ages were otherwise essentially normal. More variable features included sparse hair, short broad metacarpals and phalanges, and mild recurrent infections. Patient 3 was noted to have dysmorphic features, including wide forehead, epicanthal folds, and strabismus; this boy also had macroorchidism. The patients had impaired intellectual development; the 13-year-old patient was nonverbal.

The heterozygous mutations in the DNMT3A gene that were identified in patients with HESPJS by Heyn et al. (2019) occurred de novo.

In 3 unrelated patients with HESPJS, Heyn et al. (2019) identified de novo heterozygous missense mutations in the conserved PWWP domain of the DNMT3A gene (W330R, 602769.0008 and D333N, 602769.0009). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not found in large databases such as gnomAD or ExAC. In vitro functional expression studies using recombinant proteins showed that the W330R mutant was unable to bind H3K36me2 or H3K36me3, whereas wildtype DNMT3A was able to bind these histone peptides. The D333N mutation was predicted to have a similar effect. Analysis of patient-derived fibroblasts and peripheral blood leukocytes showed that the variants had altered chromatin binding specificity resulting in significant DNA hypermethylation of multiple genes compared to controls. Gene ontology analysis indicated that most of the hypermethylated regions likely affected genes associated with transcription and developmental processes, including HOX genes. Chromatin immunoprecipitation studies of normal cells showed that the affected differentially methylated regions (DMRs) contained CpG islands and were associated with polycomb repressive complexes (PRCs). However, regions of increased methylation in patient cells were not confined to CpG islands and extended throughout normally hypomethylated regions, termed 'DNA methylation valleys.' Patient fibroblasts showed reduced H3K27me3 levels at the DMRs compared to controls, suggesting disruption of PRC2 binding and activity. Expression of the orthologous W326R mutation in murine embryonic stem cells caused DNA hypermethylation at the DMRs during differentiation to embryoid bodies and to neural progenitor cells; RNA sequencing of these mutant murine cells and W330R fibroblasts showed abnormal expression of transcription factors that tended to skew toward differentiation and away from self-renewal. Heterozygous mutant mice had reduced brain size and body weight, and were proportionately small compared to controls. Hypermethylation at the DMRs were observed in neurons in the mouse cerebral cortex. Heyn et al. (2019) concluded that the DNMT3A mutations result in a gain-of-function effect, causing hypermethylation at polycomb-marked developmental genes during early stages of cell fate specification and differentiation.