Pure duplication of 19p13.3 in three members of a family with intellectual disability and literature review. Definition of a new microduplication syndrome

Abstract

This paper describes the presence of an interstitial pure duplication of 19p13.3 (4.95 Mb) in a patient with intellectual disability studied by array-CGH which was initially considered as a de novo alteration. The discovery of the same chromosomal alteration in a first-degree cousin of this patient led us to investigate the presence of insertional translocations, which were consequently found in three family generations. The same duplication was found in three intellectually disabled patients and among the translocation carrier family members a very high incidence of miscarriages are reported. A review of other published cases has allowed us to find three other patients with a similar pure duplication, all of them sharing some common clinical findings such as intrauterine growth retardation, microcephaly, motor and speech delay, moderate to severe intellectual disability, and dysmorphic features. These findings allow us to suggest the presence of a new microduplication syndrome in chromosomal region 19p13.3.

Nonmosaic Trisomy 19p13.3p13.2 Resulting from a Rare Unbalanced t(Y;19)(q12;p13.2) Translocation in a Patient with Pachygyria and Polymicrogyria

“…Chromosome 19 abnormalities are very uncommon compared to those found in other chromosomes of the human karyotype [Orellana et al, 2015]. In addition, Y;autosome translocations are infrequent genomic rearrangements that appear in 1/2,000 individuals in the general population and commonly involve an acrocentric chromosome [Wang et al, 2017].…”

“…2 ; Table 1 ). However, they do not present a typical CFC4 phenotype because they lack other distinctive features, such as thin and curly hair [Siggberg et al, 2010;Nowaczyk et al, Cytogenet Genome Res 2020;160:177-184 DOI: 10.1159/000507561 182 2014; Nevado et al, 2015;Orellana et al, 2015;Novikova et al, 2017].…”

“…We cannot exclude that the overexpression of this gene resulting from trisomy 19p could have a deleterious effect on the stability of microtubules, which has been associated with brain malformation and abnormal neuron positioning. Regarding this, Orellana et al [2015] and Seidel et al [2014] described 2 patients with brain malformations and trisomy 19p that must involve the TUBB4A gene ( Fig. 2 ; Table 1 ).…”

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

“…Later on, several independent groups suggested that this new duplication syndrome included a similar SRO at 19p13.3. 6,7 Ubiquitin E3 ligases represent a large family of proteins, which are involved in many cellular pathways by regulating the expression of other proteins through the proteasome. 8 Pathogenic variants in these genes are related to different diseases, including cancer, immune, neurodegenerative and endocrine disorders.…”

“…Clinical features include abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with DD, hypotonia, speech delay, abnormality of the esophageal function, abnormalities of the limbs, umbilical hernia and common dysmorphic features. Later on, several independent groups suggested that this new duplication syndrome included a similar SRO at 19p13.3 …”