P362: Newborn with 4 syndromes (Down, Turner, Xp11.22 duplication and 3q duplication) characterized by G-banding, FISH, microarray and optical genome mapping

A newborn of 38 completed weeks of gestation had complete AV canal, hemolytic disease of newborn due to isoimmunization, thrombocytopenia, abnormal hearing screen and features of trisomy 21. G-banding showed a mosaic female karyotype 47,X,add(X)(p11.2),+21[10]/47,XX,+21[6]/46,X,+21[5] with +21 in all 21 cells analyzed, add(X)(p11.2) in 10 cells, and monosomy X in remaining 5 cells. Whole genome microarray (CytoScan Dx, Thermo Fisher) identified 4 abnormalities: 21q duplication, consistent with Down syndrome; ∼52.7 Mb deletion of distal Xp at Xp22.33p11.22 including the SHOX gene, together with monosomy X by G-banding, consistent with Turner syndrome; ∼3.3 Mb duplication of proximal Xp at Xp11.22p11.21 including the HUWE1 gene, consistent with Xp11.22 duplication syndrome (OMIM 300705) or X-linked syndromic intellectual disability; and ∼25.1 Mb duplication of distal 3q at 3q26.31q29, consistent with 3q duplication syndrome (PMID: 30140197, 12372060, 27549440). These abnormalities were all interpreted de novo based on normal parental findings by G-banding, FISH and microarray. Sequential telomere FISH and G-banding confirmed the presence of der(X)t(X;3)(p11.22;q26.31) leading to deletion of distal Xp and duplication of distal 3q. The clinical findings of Xp11.22 duplication syndrome include mild-severe intellectual disability, speech delay, dysmorphic features, early puberty, constipation, and/or hand and foot abnormalities (PUBMED: 26692240, 20655035, 22840365). The clinical presentation of 3q duplication syndrome varies, including typical facial dysmorphism, hirsutism, microcephaly, intellectual disability, growth retardation, genitourinary anomalies, hand and feet abnormalities, and renal and congenital heart defects. About 1/3 of 3q duplication patients do not survive their 1st year of life and die from heart malformations and infections (PMID: 12372060). Optical genome mapping (OGM) confirmed all of these anomalies. Further, OGM identified the der(X)t(X;3)(p11.22;q26.31) with molecular breakpoints at chrX:56,258,258 and chr3:172,741,632 and Xp11.22p11.21 duplication being inv dup. To the best of our knowledge, this is probably the 1st reported case with cytogenomic anomalies indicative of 4 syndromes.