P458: Considerations and challenges in genetic testing for hypermobile Ehlers-Danlos syndrome (hEDS): A multidisciplinary overview

Outcome and Follow-Up: The family presented to our clinic for counseling on the significance of the balanced translocation and COL11A2 VUS.Review of in silico evidence and clinical correlation did not raise suspicion for Stickler syndrome.While it is unlikely for balanced translocations to cause symptoms, this translocation appears to segregate with a particular phenotype in the proband and subsequent pregnancy.Considering the negative ES, the family was counseled on the possibility of the balanced translocation leading to the observed features.These conclusions may help to inform future family planning.Discussion: Disruptions to long range regulatory elements surrounding SOX9 have been implicated in variable phenotypes ranging from campomelic/ acampomelic dysplasia to isolated PRS.The distance of genomic alterations from SOX9 has been correlated with phenotypic severity in SOX9-related disorders, however some reports suggest variability is more likely to represent incomplete penetrance or variable expressivity.Nevertheless, while PRS has been observed with disruptions upstream of SOX9, to our knowledge, cases of isolated PRS have not been observed at the 17q23 locus.This case could represent a susceptibility to isolated PRS at a locus further upstream of SOX9 than previously reported.However, it remains difficult to definitively elucidate the influence of the translocation breakpoint at 17q23, the COL11A2 VUS, or a multifactorial model for the features within this family. Conclusion:The etiology of PRS is often unknown; however, disruptions surrounding SOX9 have been linked to PRS.The results reviewed here present a challenge for the clinicians and family alike.In cases like ours, the diagnostic challenge complicates the ability of clinicians to accurately inform recurrence risks and has the potential to be a source of confusion and anxiety for families.This case may challenge the assumption that balanced translocations do not cause symptoms and widen the established regulatory region upstream of SOX9 that can cause symptoms when disrupted.Further research could explore the 17q23 locus and its association with PRS.Introduction: Balanced translocations are not generally known to cause symptoms.However, there have been reports of balanced translocations with breakpoints surrounding SOX9 at 17q24.3 in which campomelic/acampomelic dysplasia and Pierre Robin Sequence (PRS) phenotypes with varying clinical severity have been observed.We present a pediatric patient with a balanced translocation including a breakpoint at 17q23 and isolated PRS.This case may expand the region upstream of SOX9 known to be associated with symptoms.Case Presentation: The proband presented in utero with increased nuchal translucency (NT), cystic hygroma and micrognathia.At birth, a cleft palate and PRS were confirmed.Neonatal history was significant for failure to thrive.At 3 years, he exhibited continued difficulty with weight gain without other delays.He had no obvious dysmorphic features or skeletal anomalies on clinical examination.The proband's father had a history of bifid uvula, unilateral hearing loss, and mild scoliosis.He reported a possible clubfoot, requiring bracing in infancy.A subsequent pregnancy for the proband's parents carried the balanced translocation and was terminated due to an increased NT and significant micrognathia.Diagnostic Workup: Karyotype, Noonan syndrome panel and SOX9 single gene were completed on CVS sample of the proband.Karyotype revealed a paternally inherited balanced translocation: 46, XY t(4;17)(q12q23)PAT.At 1-year chromosomal microarray analysis (CMA) and Stickler syndrome panel were completed, revealing a paternally inherited variant of uncertain significance (VUS) in COL11A2 (c.1002G>C, p.E334D).CMA was negative.The COL11A2 VUS was inherited from the asymptomatic paternal grandfather.The translocation was de novo in the proband's father.To rule out alternative genetic etiologies for PRS, trio exome sequencing (ES) was completed and was negative.Notably, genome sequencing on the terminated pregnancy was negative, including the COL11A2 VUS.