Kids First: Genomic Etiologies of CHARGE Syndrome, Related Conditions and Structural Anomalies

Developmental disorders with structural birth defects account for the majority of morbidity and mortality in children's hospitals, and the genetic bases of many clinical phenotypes remain unknown. Genetic testing for individuals with structural malformations has uncovered the basis of many such birth defects; however, many more cases remain unsolved, posing challenges for diagnosis, treatment, and prevention. Multiple anomaly conditions are particularly challenging to diagnose, since they often present with unique combinations of clinical features that vary widely between affected individuals, even in the same family. CHARGE Syndrome (Coloboma of the eye, Heart Defects, Atresia of the choanae, Retardation of growth and development, Genital abnormalities including pubertal delay and infertility, Ear abnormalities with deafness and vestibular disorders) is a multiple anomaly condition that affects a wide variety of organ systems. CHARGE Syndrome is caused in most cases by monoallelic pathogenic variants in CHD7, the gene encoding ATP-dependent helicase chromodomain DNA binding protein 7. Both de novo and inherited variants in CHD7 have been reported in CHARGE, and a growing number of families present with individuals who test positive for a pathogenic CHD7 variant yet exhibit only mild features. Similarly, individuals with CHARGE Syndrome often exhibit broad variability and reduced penetrance of clinical features, consistent with pleiotropic roles for CHD7 during development and/or additional genetic contributors or modifying alleles. Recent work has also implicated RERE, KMT2D, EP300, and PUF60 in having a role in CHARGE Syndrome.We hypothesize that (1) some cases of CHARGE are due to other genetic etiologies including oligogenicity, and (2) genetic modifiers contribute to the broad clinical variability and reduced penetrance of CHARGE features. To address these hypotheses, we have generated a cohort of 223 deeply clinically phenotyped individuals with CHARGE Syndrome and related disorders and structural anomalies who tested negative by chromosomal microarray, single gene sequencing, next generation panel sequencing, or exome sequencing. These individuals exhibit clinical CHARGE-like features including structural birth defects affecting craniofacial, ocular, neurosensory, brain, heart, mediastinal, renal, genitourinary, and skeletal organs. Our cohort includes these 223 individuals as well as affected and unaffected family members who consented to clinical and research genetic testing and donated blood samples for DNA and RNA isolation and sequencing. Building on this valuable cohort, we propose to use exome and genome sequencing to identify novel genetic etiologies of CHARGE and related developmental disorders for which alternative genetic tests have been inconclusive. Identification of novel pathogenic genetic variants and contributing modifier alleles within the coding and non-coding portion of the genome of these individuals will improve genetic diagnosis and provide important insights toward understanding the developmental mechanisms of structural birth defects. ]]>
Inclusion CriteriaParent-offspring trios; children with clinical features of CHARGE and their family membersIndividuals with CHARGE-related structural and developmental anomalies Exclusion CriteriaPatients with documented exposure to teratogens, CHD7 pathogenic variants, or other genetic diagnoses ]]>
Developmental disorders with structural birth defects account for the majority of morbidity and mortality in children's hospitals, and the genetic bases of many clinical phenotypes remain unknown. Genetic testing for individuals with structural malformations has uncovered the basis of many such birth defects; however, many more cases remain unsolved, posing challenges for diagnosis, treatment, and prevention. Multiple anomaly conditions are particularly challenging to diagnose, since they often present with unique combinations of clinical features that vary widely between affected individuals, even in the same family. CHARGE syndrome (Coloboma of the eye, Heart Defects, Atresia of the choanae, Retardation of growth and development, Genital abnormalities including pubertal delay and infertility, Ear abnormalities with deafness and vestibular disorders) is a congenital disorder affecting vision, hearing, puberty, cognition, and development of craniofacial, skeletal, renal, and cardiac structures. Heterozygous pathogenic variants in the gene CHD7, which encodes an ATP-dependent chromatin remodeling protein, comprise the major genetic cause CHARGE syndrome. The majority of CHD7 variants are loss of function alleles (deletions, frameshift, or nonsense mutations), whereas a minority of variants are missense alleles or chromosomal rearrangements. Since the original report identifying the role of CHD7 in CHARGE, genetic testing has focused on evaluating coding variants as the genetic basis of this syndrome. Nevertheless, pathogenic variants in CHD7 fail to be detected in a number of individuals with clinical features of CHARGE, suggesting there are additional genetic etiologies to be identified.This study will continue to contribute to our knowledge of phenotype-genotype relationships in CHARGE syndrome. Our existing patient cohort, generated through recruitment at two prior CHARGE Foundation meetings (2015, 2017) and through the University of Michigan Mott Children's Hospital Pediatric Genetics clinic, is critical to our efforts to identify novel genetic etiologies of CHARGE syndrome in coding regions and non-coding cis-regulatory elements. Our cohort provides a foundation for future CHARGE syndrome genetic studies that can benefit from new genome sequence analysis tools to create insights into genetic mechanisms of developmental disorders. Lastly, the functional significance of novel genetic findings that contribute to CHARGE syndrome will be pursued on a research basis to provide a better understanding of the molecular pathology of these conditions. ]]>