P771: Newborn with Kagami–Ogata syndrome and upd(14)pat characterized by trio SNP array, Mendelian inheritance error and genotyping analyses

Treatment and Management: The patient is currently 10 months old and was discharged from the NICU after a 9-month hospitalization which included, at age ~5 months, insertion of tracheostomy to support her chronic respiratory failure and a gastrostomy tube to support feedings.Alpha fetoprotein levels are being monitored every 3 months for hepatoblastoma.Outcome and Follow-Up: Since discharge, the patient is being followed by an interdisciplinary group of providers for ongoing medical issues.Recommended follow-up of individuals with KOS includes ongoing monitoring and treatment of developmental delay/intellectual disability/educational needs, respiratory failure, treatment of skeletal abnormalities (kyphoscoliosis, joint contractures, coxa valga), feeding difficulties/poor weight gain, cardiac issues (annual echocardiogram), hepatoblastoma (abdominal ultrasound, serum alphafetoprotein every 3 months until age 3-4 years), and social work/family support.Discussion: Ogata and Kagami proposed that diagnosis of KOS should begin with simultaneous methylation analysis of MEG3:TSS-DMR and deletion analysis of multiple loci (MEG3/DLK1:IG-DMR, MEG3:TSS-DMR, and RTL1as) at the 14q32.2imprinted region by MS-MLPA.If methylation is abnormal but no deletion is identified, parent-of-origin testing can distinguish upd( 14)pat from an epimutation.If upd( 14)pat is confirmed, karyotyping is recommended to evaluate for Robertsonian translocations or isochromosome 14.If methylation is normal and a 14q32.2deletion is identified, second-tier testing can confirm if the deletion is maternal.Because MS-MLPA for KOS is not widely available while SNV microarray testing is, our approach using trio SNV array in combination with karyotyping may enable a cost-effective definitive and rapid result (within 1 week), clarify recurrence risk, and help rule out mechanisms that MS-MLPA cannot, including uniparental heterodisomy.Conclusion: Our results emphasize that trio SNV microarray, MIE, and genotyping may be a better alternative to diagnose upd( 14) and also other upd syndromes over conventional testing modalities as discussed in our previous publication.Introduction: Kagami-Ogata syndrome (KOS) is a very rare genetic disorder with ~100 individuals identified to date.KOS is characterized by a severe phenotype with polyhydramnios, thoracic dysplasia (coat-hanger sign on X-rays) with respiratory failure, abdominal wall defects, poor growth, developmental delay, feeding difficulty, and facial abnormalities.Additional features may include skeletal abnormalities, cardiac disease and hepatoblastoma.Mortality is ~20% before age 5 and is often due to respiratory failure.Paternal uniparental disomy for chromosome 14 (upd( 14)pat)) accounts for ~50% of cases; microdeletions of maternal chromosome 14 and epimutations account for the remaining cases.Recommended methylation-specific multiplex ligationdependent probe amplification (MS-MLPA) KOS testing may not be widely available.We report a widely available method which allows for a rapid and accurate diagnosis with timely counseling and clinical management.Case Presentation: The female patient was born prematurely at 31 weeks due to polyhydramnios, gestational diabetes, and prenatal concerns for multiple congenital anomalies.Notable anomalies included a bell-shaped chest, abnormal hand posturing, levorotation of the heart, and a small stomach.Diagnostic Workup: A 358 gene skeletal dysplasia sequencing panel revealed a VUS in the MNX1 gene that was not consistent with the patient's phenotype.Rapid exome sequencing was negative.Affymetrix microarray CytoScan Dx analysis showed no clinically significant deletions or duplications.However, SNV microarray analysis showed upd(14).Mendelian Inheritance Error (MIE) analysis of the proband, father and mother showed that chromosome 14 MIEs were significantly high for the trio (11.97%) and mother (11.59%) and significantly low for the father (0.01%); indicative of upd( 14)pat.The proband had homozygous genotype calls of either AA or BB (no AB) for the entire 14q, confirming paternal uniparental isodisomy.The proband and parents all had normal karyotypes by G-banding.Findings of paternal isodisomy were confirmed by concurrent PCR-based microsatellite analysis and are consistent with a diagnosis of KOS and a recurrence risk to sibs of <1%.