Distinctive Phenotypic Abnormalities Associated with Submicroscopic 21q22 Deletion Including DYRK1A

Abstract

Partial monosomy 21 has been reported, but the phenotypes described are variable with location and size of the deletion. We present 2 patients with a partially overlapping microdeletion of 21q22 and a striking phenotypic resemblance. They both presented with severe psychomotor delay, behavioral problems, no speech, microcephaly, feeding problems with frequent regurgitation, idiopathic thrombocytopenia, obesity, deep set eyes, down turned corners of the mouth, dysplastic ears, and small chin. Brain MRI showed cerebral atrophy mostly evident in frontal and temporal lobes, widened ventricles and thin corpus callosum in both cases, and in one patient evidence of a migration disorder. The first patient also presented with epilepsy and a ventricular septum defect. The second patient had a unilateral Peters anomaly. Microarray analysis showed a partially overlapping microdeletion spanning about 2.5 Mb in the 21q22.1–q22.2 region including the DYRK1A gene and excluding RUNX1. These patients present with a recognizable phenotype specific for this 21q22.1–q22.2 locus. We searched the literature for patients with overlapping deletions including the DYRK1A gene, in order to define other genes responsible for this presentation.

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

“…There were some strikingly similar features between members of our cohort and the features of previously reported individuals with a similar genotype, [10][11][12][13][14][15][16][17] indicating that this is a recognizable syndrome. Microcephaly, IUGR, brain abnormalities consistent with cerebral hypomyelination, global DD, ID, severe speech delay, seizures, broadbased gait, short stature, minor skeletal anomalies, and distinct facial gestalt were the most commonly shared features.…”

“…Interestingly, the sister (P10) is mosaic for the deletion with a normal cell line in the minority, and has a dizygotic unaffected twin brother (Supplementary Figure S1). A mosaic deletion was also detected in P13 by FISH studies, and in two published cases 14,16 (Supplementary Figure S2). P13 and P14 have the largest deletions.…”

“…[10][11][12][13][14][15][16] These are included in Supplementary Table S1. Specific evidence supporting the role of DYRK1A individuals includes the deletion of the non-coding 5′-UTR (NM_130436.3) in one published case, 11 as well as the disruption of DYRK1A by translocation in two cases reported by Moller et al 10 Furthermore, in the Database of Genomic Variants, there are only two self-reported phenotypically normal individuals with exonic losses of DYRK1A (8 Kb and 181 Kb).…”

“…A clinical geneticist provided phenotypic information for all patients. The clinical features of our cohort (n = 14, Table 1) are summarized and were assessed for both overlap and divergence among the cohort and compared with the 13 individuals in published reports, [10][11][12][13][14][15][16][17] as shown in Supplementary Table S1.…”

“…5,6 Furthermore, data from both animal models and humans have suggested that decreased DYRK1A expression is also pathogenic. [7][8][9] Pathogenic variants in DYRK1A resulting in haploinsufficiency of the gene have recently been proposed to cause intellectual disability (ID), mental retardation autosomal dominant type 7 (MIM 614104) in individuals with translocations, 10 single-nucleotide variants (SNVs), 11,12 and intragenic microdeletions 11,[13][14][15][16][17] disrupting only DYRK1A.…”