HudsonAlpha Long Read Sequencing Data of Individuals with Rare Suspected Genetic Conditions

The data included in this project were generated from several IRB projects focused on the identification of the underlying genetic cause of undiagnosed rare conditions in infants, children and adults enrolled across the southeastern United States. Long read genome sequencing was performed on DNA samples collected as part of an IRB-approved study and findings from this testing was returned to enrolled study participants and the clinical team providing care. Proband participants in these studies were enrolled in both inpatient (neonatal intensive care units) and outpatient settings. When possible, biological relatives (including both biological parents) were also enrolled to help clarify inheritance of variants identified. Sequencing and analysis for SouthSeq is conducted at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama (https://www.hudsonalpha.org/). Results of testing are disclosed to participants by genetic counselors or trained non-genetics providers who also facilitate sharing of results with the participants' medical care teams when appropriate. Further, participant families may choose to opt-into return of secondary findings identified in the proband, which focus on pathogenic and likely pathogenic variation identified within the current ACMG gene list.]]>
Though the criteria for inclusion and exclusion in each of these studies were not identical, there was significant overlap as outlined below: The enrolled probands present with a major medical condition, such as seizures, metabolic abnormality, or conjugated hyperbilirubinemia, for which the primary care team does not know of an obvious etiology. "Obvious etiology" refers to a genetic, infectious, or environmental cause that has been or can be rapidly confirmed by history and/or laboratory testing, e.g. intraventricular hemorrhage associated with significant prematurity, seizures associated with an inborn error of metabolism for which a molecular diagnosis can be confirmed. For SouthSeq, infants who otherwise would have met inclusion criteria, but passed away during the time that the study was actively enrolling participants (including those with abnormalities detected prenatally then born deceased or passing away shortly after delivery) were also enrolled, provided that blood samples were available and parents consented to participate in the study. Individuals were excluded from the study if they had:- a pattern of findings and/or abnormalities consistent with known or strong suspicion for a chromosomal aneuploidy (Ts13, 18, 21, Monosomy X);- isolated anomalies known to have a low diagnostic yield for Mendelian causes, e.g. gastroschisis, hydronephrosis;- a pattern of findings and/or abnormalities consistent with confirmed teratogenic exposures, e.g. hydantoin, valproate;- a pattern of findings and/or abnormalities consistent with confirmed congenital infection, e.g. TORCH.Additional Comments:Patients with suspected Down syndrome or life-threatening whole chromosome aneuploidies in which acute clinical care depends on a diagnosis, e.g. Ts13 or Ts18, were not enrolled, but patients with congenital anomalies for which a clinical chromosomal microarray would otherwise be obtained were offered enrollment.Patients with a history of potential teratogenic exposures or congenital infection may have been eligible for inclusion if there are congenital anomalies and/or conditions that are not explained by the potential teratogen or infection. In this situation, one of the study investigators was consulted.Testing performed as part of these research studies was not intended to replace routine clinical care. Patients were also provided standard of care clinical genetics consultation, which may have included microarray/array CGH. If the array result was abnormal, the research team had the opportunity to decide if sequencing was appropriate. We intended to keep these criteria broad to allow for the enrollment of individuals with rare symptoms and avoid exclusion of those who might benefit from genome sequencing.When possible, biological parents of the proband were also enrolled, whether they were affected or unaffected with a rare disease, for the purpose of confirming inheritance of variants of interest. ]]>
Enrollment is closed for CSER1, SouthSeq and PGEN. AGHI and Long-Read Genomic Sequencing of Individuals with Neurodevelopmental Disorders are open for enrollment. CSER1: Study enrollment opened 2014 - 2018; n=532 probandsSouthSeq: Study enrollment opened February 2018 - July 2021; n=640 probandsPGEN: Study open for enrollment AGHI: Study open for enrollmentLong-Read Genomic Sequencing of Individuals with Neurodevelopmental Disorders: Study open for enrollment]]>