Pallister-Killian Mosaic Syndrome

CLINICAL UPDATE Case study 4: Pallister-Killian mosaic syndrome

Hx Finding 12

33 YEAR OLD FEMALE LATE TO CARE 27 WEEKS GA MATERNIT® GENOME Ultrasound findings (NOS–not ORDERED AT 27 WEEKS otherwise specified) Positive: 34.3Mb gain 12(p11.1-p13.33) This region has been reported to be involved in Pallister-Killian mosaic syndrome

Normal 50 Kb trace

1.4 (for comparison) Each number represents a chromosome, from 1 to 22, X/Y. 1.2 Note that the orange line stays relatively flat in a normal trace. 1.0 0.8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 2122 X Y 0.6

0 10000 20000 30000 40000 50000

50kb bins

Positive MaterniT

1.4 GENOME trace Note the significant upward deviation on the orange line for chromosome 1.2 12p, signifying a gain of material on that genomic location. 1.0 0.8

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 2122 X Y 0.6

0 10000 20000 30000 40000 50000

50kb bins

Key points • MaterniT GENOME correctly identified complex chromosomal abnormalities consistent with Pallister-Killian mosaic syndrome, confirmed by diagnostic testing (Microarray and Karyotype) • According to Genetics Home Reference, “Pallister-Killian mosaic syndrome appears to be a rare condition, although its exact prevalence is unknown. This disorder may be underdiagnosed because it can be difficult to detect in people with mild signs and symptoms. As a result, most diagnoses are made in children with more severe features of the disorder. More than 150 people with Pallister-Killian mosaic syndrome have been reported in the medical literature.”1 • Esoteric findings including Pallister-Killian are individually rare, but collectively common, and not potentially associated with advanced maternal age.2 Using an advanced NIPT screening test like MaterniT GENOME offers more clinically relevant information to the clinician and patient • As illustrated by this case study, using traditional NIPT and screening for only common aneuploidies (T13/18/21) with cfDNA may miss clinically relevant abnormalities on other chromosomes, potentially delivering false reassurance

MaterniT GENOME detects up to 30% more chromosomal information than other NIPTs3,4; detects chromosomal aneuploidies missed by traditional NIPT; thereby providing earlier awareness and more proactive pregnancy management options.

1617200331−NIK−4−46, chr12p13.33p11.1, base: 200001:34500000, size(Mb): 32.15 [34.3], CBS z−score: 39.01, CBS LOR: 1000, chr z−score: 18.51, chr LOR: 62.91, CBS est FF: 0.15, chrXFF: 0, bff: 0.238, profile SD: 0.0421, bst_subchr: 1, maternal: FALSE,

gneg gpos25

2.0 gpos50 gpos75 gpos100 acen q12 p13.2 p12.3 q14.1 p12.1 p11.1 q13.2 q14.3 q21.1 q23.1 q23.3 stalk p11.22 q13.12 q21.31 q24.21 q24.23 q24.32 p13.32 q21.33 q24.12 gvar normal

1.5 fullDtect q11 q15 q22 p12.2 q14.2 p13.1 q23.2 q13.3 q21.2 highConf q21.32 q24.11 q24.31 p13.33 p13.31 p11.23 q13.11 q13.13 q24.13 q24.22 q24.33 p11.21 1.0 SPCA Profile 0.5

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140

Genomic Location (Mb) Chromosome 12 – 34.3Mb gain 12(p11.1-p13.33)

Ideogram from the MaterniT GENOME lab report with close-up view of the impacted chromosomal trace provide a detailed view of the region of interest. The purple trace shows the deviation: a gain on chromosome 12p. (Note the purple trace in relation to the blue trace.)

Case study 4 summary • Patient late to care • 27 weeks GA – Ultrasound findings: positive; club foot, diaphragmatic hernia, increased nuchal fold, patient initially refused amniocentesis • 27 weeks GA – MaterniT GENOME ordered (ultrasound findings not disclosed to the lab); positive for gain of chromosome 12p • 28 weeks GA – Amniocentesis with microarray reported 80% mosaicism i(12p) consistent with Pallister-Kilian syndrome. Karyotype showed isochromosome 12p in all metaphase cells • Will pursue palliative care upon delivery

Results from case studies are not predictive of results in other cases. Results in other cases may vary.

1. US National Library of Medicine. Genetics Home Reference. Pallister-Killian mosaic syndrome. https://ghr.nlm.nih.gov/ condition/pallister-killian-mosaic-syndrome. Accessed January 9, 2018. 2. Blyth M, Maloney V, Beal S, et al. Pallister-Killian syndrome: a study of 22 British patients. J Med Genet 2015;52:454-464. 3. Ehrich M, Tynan J, Mazloom A, et al. Genome-wide cfDNA screening: clinical laboratory experience with the first 10,000 cases.Genet Med. 2017;19(12):1332-1337. 4. Internal data