Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

Abstract

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

Figure 1

Pictures of seven patients with DYRK1A-associated ID described in this study. Note the common clinical features among most of the patients, including microcephaly, deep-set eyes, protruding ears, long and flat philtrum with thin upper vermilion and micrognathia. The corresponding patient numbers are as follows: (a) #1, (b) #2, (c) #3, (d) #4, (e) #5, (f) #9 and (g) #10.

Figure 2

Schematic depicting the approximate locations of all the truncating and missense mutations, deletions and chromosomal rearrangements affecting DYRK1A (NM_001396.3). Truncating and missense mutations (gray stars), translocation breakpoints (lightning symbols) and microdeletions (rectangles) of the previously published cases with DYRK1A syndrome. Black-colored stars represent the approximate location of mutation sites within the DYRK1A locus of patients presented in this paper. Idiogram of human chromosome 21 (GRCh37/hg19 assembly) was obtained from the UCSC genome browser website.