Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor

Abstract

The proximal 19p13.3 microdeletion/microduplication (prox19p13.3del/dup) syndrome is a recently described disorder with common clinical features including developmental delay, intellectual disability, speech delay, facial dysmorphic features with ear defects, anomalies of the hands and feet, umbilical hernia and hypotonia. While deletions are associated with macrocephaly, patients with duplications have microcephaly. The smallest region of overlap in multiple patients (113.5 kb) included three genes and one pseudogene, with a suggested major role of PIAS4 in determination of the phenotype and head size in these patients. Here, we refine the prox19p13.3del/dup with four additional patients: two with microdeletions, one with microduplication and one family with single‐nucleotide nonsense variant in PIAS4. The patient with the PIAS4 loss of function variant displayed a phenotype quite similar to deletion patients ‐including the macrocephaly and many other core features of the syndrome. Patient's SNV was inherited from her mother who is similarly affected. Thus, our data indicate that PIAS4 is a major contributor to the proximal 19p13.3del/dup syndrome phenotype. In summary, we report the first patient with a pathogenic variant in PIAS4‐ and three additional rearrangements at the proximal 19p13.3 locus. These observations add further evidence about the molecular basis of this microdeletion/microduplication syndrome.

A rare intrauterine onset growth retardation syndrome caused by mosaic 19p13.3 microduplication: evaluation of GH/IGF- 1 axis and GH therapy response

“…Table I summarizes the clinical findings in our patient and in previously reported patients with pure 19p13.3 duplications. [1][2][3][4][5][6] The majority of subjects including our patient had microcephaly (7/10). One of the normocephalic patients had a duplication without PIAS4 gene, and the other patient with borderline microcephaly had a partial PIAS4 gene duplication.…”

“…19p13.3 microduplication syndrome is a newly defined intrauterine onset growth retardation syndrome characterized by microcephaly, moderate intellectual disability, speech delay, and mild dysmorphic features. [1][2][3][4][5][6] The 19p13.3 region includes PIAS4, ZBTB7A, and MAP2K2 genes, which were thought to be responsible for the characteristic findings of the syndrome. It was hypothesized that PIAS4 gene duplication has the essential role for microcephaly and intrauterine growth retardation.…”

“…It was hypothesized that PIAS4 gene duplication has the essential role for microcephaly and intrauterine growth retardation. 5,6 PIAS4 protein is a member of the E3 SUMO-protein ligase family. It regulates histone modifications and plays a crucial role in transcriptional coregulation, genetic stability, and various cellular pathways like STAT, p53/TP53, Wnt, and steroid hormone signaling pathways.…”

“…Recently a case with single nucleotide variant in PIAS4 that has common characteristics of 19p13.3 microdeletion syndrome was reported, supporting the hypothesis of PIAS4 effect on head circumference and growth. 6 Nevado et al 1 also evaluated the clinical findings of eleven patients with 19p13.3 microdeletion and two patients with 19p13.3 microduplication in a study in 2015. While one of the patients with microduplication without PIAS4 duplication was normocephalic and short statured, the other patient with PIAS4 duplication had microcephaly (-4 SDS) and short stature.…”

“…Duplications and deletions of this region were reported in about 50 patients, the majority of which were deletions. [1][2][3][4][5][6] Siggberg et al 3 reported microcephaly, intrauterine onset growth retardation and 0.8 Mb-long duplication on 19p13.3 (chr:19: 1952590_6908729) in three patients from a family with similar clinical features (microcephaly, moderate to severe intellectual disability, speech delay and dysmorphic findings) and defined the 19p13.3 microduplication syndrome. Andries et al 7 also earlier reported a case that has similar characteristics of the syndrome with pure terminal duplication of the short arm of chromosome 19.…”