Supplemental Data Includes Three figures, Two Tables and List of Web Resources

Supplemental Data

Supplemental Data includes three figures, two tables and list of Web resources.

Figure S1:Mosaic microdeletion including DRYK1A found in P10 and P11.

A:Pedigree information for P10 and P11 with mosaic DYRK1A deletion. The mother carries a balanced intrachromosomal insertion on chromosome (chr) 21 [ins(21)(p13q22.13q22.13)], and the two siblings have the abnormal recombinant 21 with a microdeletion B: Microarray plot shows log2 ratio -1, and deletion on chr 21 involving DYRK1A (arr[hg18] 21q22.13q22.2(37,662,974-39,195,976)×1). C: Metaphase FISH performed on the female proband’s lymphocytes with BAC probe RP11-1021I19. Right: 90% of the metaphase cells (45/50) showed loss of red signal indicating deletion of target locus; Left: 10% of the cells (5/50) showed two normal copies and position of the spectrum orange signal (no deletion).

Figure S2. Evidence of the mosaic microdeletion found in P13

A. This is a de novo deletion. B. Microarrayplot. The deleted region is represented by the red bar; log2 ratio -0.5-1.0, copy number state of 1, shift in the allele difference of the oligonucleotides with a SNP. The region overlaps with the DSCR and contains and 30 RefSeq genes:C21orf88, CHAF1B, PIGP, KCNJ6, ERG, HMGN1, B3GALT5, CLDN14, TTC3, DSCR4, ETS2, WRB, IGSF5, SIM2, DSCR9, DSCR8, PSMG, LCA5L, PCP4, DOPEY2, HLCS, DSCR3, DSCR10, BRWD1, SH3BGR, DSCAM, MORC3, DSCR6, DYRK1A and KCNJ1.The common deleted region on Braddock-Carey syndrome (BCS) is centromeric to our patient’s region (orange arrow) C: FISH analysis on proband’s lymphocytes with the DSCR probe (LSI 13/21 AneuVysion Abbott, Inc). These studies confirmed a deletion of 21q22 in 92% of the metaphases (arrowhead), and interphase nuclei (arrows) indicative of a mosaic pattern with a small percentage (8%) of normal cells having two normal copies of 21q22 (spectrum orange signal, arrows).

Figure S3. Pedigrees of DYRK1A variants found in our cohort. Sanger sequencing chromatograms of seven of the nine patients with SNVs are shown.

Table S1: Comparison of genetic and phenotypic characteristics of the published patients with DYRK1A disruption and our patient cohort. Blank indicates not available, not applicable or not measured; + and − signs indicate the presence or absence of clinical feature in the patient; Genomic coordinates of Hg19 were used; DYRK1A reference sequence number: NM_001396.3; del, deletion; SD, standard deviation; ASD, autism spectrum disorder; dn, de novo; IUGR, intrauterine growth restriction.

Table S2: Tests ordered prior to chromosomal microarray or clinical exome sequencing and additional variants identified by CES or CMA in our patient cohort.DYRK1A reference sequence number is NM_001396.3.

Web Resources:

UCLA Clinical Genomics Center,

Enzyme Nomenclature,

HUGO Gene Nomenclature Committee (HGNC),

The Human Protein Atlas, DYRK1A,

NHLBI Exome Sequencing Project (ESP) Exome Variant Server,

Online Mendelian Inheritance in Man (OMIM),

PolyPhen-2,

SIFT,

Protein Data Bank (PDB),

RefSeq,

UCSC Genome Browser,

UniProt,

Genereviews,

Database of Genomic Variants,

WHO growth charts,

Decipher,