HudsonAlpha Institute for Biotechnology Clinical Sequencing Exploratory Research (CSER): Genomic Diagnosis in Children with Developmental Delay

The overarching goal of this project is to explore the ability for whole exome and genome sequencing technologies to identify the genetic causes of unexplained developmental delay, intellectual disability (DD/ID), and related congenital anomalies in children. Such information may be useful as an endpoint to the otherwise fruitless "diagnostic odyssey" that many DD/ID affected families undergo and in some cases, identification of these genetic variants may point to better therapeutic or educational options by precisely defining the root cause(s) of the child's condition. We seek to identify causal, diagnostically relevant, genetic variants in children with developmental delay and/or intellectual disability (DD/ID). In addition, because our analytical approach includes sequencing probands and their parents (parent-offspring trios and duos; parents are sequenced when available), secondary findings will be returned to adults (parents) at their request. The aims of this research project include: 1) Use exome and whole genome sequencing to identify genetic variation that results in DD/ID. 2) Return primary genetic results (DD/ID causative) as well as secondary findings to probands and their parents, respectively. 3) Understand how the return of genomic test results affects the health and well-being of study participants. The children participating in this study are patients at, or referrals to, North Alabama Children's Specialist (NACS) in Huntsville, Alabama. All blood samples from probands and their parents will be collected at NACS (project 1). Sequencing will be completed at the HudsonAlpha Institute for Biotechnology, with validation (via Sanger sequencing) conducted at Emory University for all returned variants (project 2). The University of Louisville will oversee questionnaires, surveys and interviews aimed at understanding study participants' perception of, and response to, genetic test results, in addition to assessment of secondary findings preferences (project 3).A subset of variants, largely those determined to be diagnostic or variants of uncertain significance for study participants at the time of disclosure, have been submitted to ClinVar. These variants are listed as part of the "CSER-HudsonAlpha" study within the database. ]]>
The range and diversity of genetic causes for DD/ID or rare undiagnosed disease is mirrored by the profusion of phenomenological diagnoses (and associated ICD-9 codes) applied to affected children. Consequently, absolute inclusion criteria based on ICD-9 codes or other specific features are unlikely to be helpful. Instead, the primary criteria for study inclusion will be the conclusion by the participants' physician that a subject has moderate to severe DD/ID that is thought to be genetic in nature and is not accounted for by known causes. The ability and willingness of one or both biological parents to participate in the study is desirable but not necessary. Details about inclusion and exclusion criteria are included below. Inclusion criteria: Parent(s) or guardian(s) is >/=19 years of age. If parent is a biological parent and wishes to participate in the study, parent is competent to consent to her/his own research participation. If parent is a biological parent and wishes to participate in the study, parent is willing to have blood drawn and receive genetic results. Parent(s) or guardian(s) is willing to complete two clinic visits (one for consent and blood draw, another for return of genetic results). Parent(s) or guardian(s) with custodial authority are willing to consent to the proband child's participation. Parent(s) or guardian(s) is able to communicate in English. Child weighs at least 9 kilos (19.8 lbs.) Has at least one parent or guardian able to consent to his or her participation in study. Child has been diagnosed with a significant developmental delay and/or intellectual disability, with or without congenital structural or functional anomalies. Exclusion criteria: Proband child's parent(s) or guardian(s) unable or unwilling to consent to child's participation. A specific genetic or environmental etiology for DD/ID or rare undiagnosed disease has already been diagnosed (including genetic or chromosomal syndromes or teratogen exposure syndromes). NOTE: Children with functional diagnoses (e.g., autism spectrum disorder) and/or symptom-based diagnoses (e.g., seizure disorder) are not excluded from participation. ]]>
June 2013: Enrollment of first participant family August 2013: First participant's whole exome sequenced November 2013: First VRC to discuss whole exam sequence data May 2014: Enrollment of 100th family January 2015: Laboratory began whole genome sequencing in lieu of whole exome sequencing February 2015: First VRC to discuss whole genome sequence data April 2015: Enrollment of 200th family February 2016: Enrollment of 300th family November 2016: Enrollment of 400th family December 2016: dbGaP study release 2 makes available sequencing data of additional n=545 study participants. April 2018: dbGaP study release 3 makes available sequencing data of additional n=440 study participants.September 2021: dbGaP study release 4 increases the total to 1413 available sequences including 16 PacBio (long read) samples. ]]>