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1.
Genome Med ; 16(1): 112, 2024 Sep 13.
Article in English | MEDLINE | ID: mdl-39272130

ABSTRACT

BACKGROUND: X-linked acrogigantism (X-LAG; MIM: 300942) is a severe form of pituitary gigantism caused by chromosome Xq26.3 duplications involving GPR101. X-LAG-associated duplications disrupt the integrity of the topologically associating domain (TAD) containing GPR101 and lead to the formation of a neo-TAD that drives pituitary GPR101 misexpression and gigantism. As X-LAG is fully penetrant and heritable, duplications involving GPR101 identified on prenatal screening studies, like amniocentesis, can pose an interpretation challenge for medical geneticists and raise important concerns for patients and families. Therefore, providing robust information on the functional genomic impact of such duplications has important research and clinical value with respect to gene regulation and triplosensitivity traits. METHODS: We employed 4C/HiC-seq as a clinical tool to determine the functional impact of incidentally discovered GPR101 duplications on TAD integrity in three families. After defining duplications and breakpoints around GPR101 by clinical-grade and high-density aCGH, we constructed 4C/HiC chromatin contact maps for our study population and compared them with normal and active (X-LAG) controls. RESULTS: We showed that duplications involving GPR101 that preserved the centromeric invariant TAD boundary did not generate a pathogenic neo-TAD and that ectopic enhancers were not adopted. This allowed us to discount presumptive/suspected X-LAG diagnoses and GPR101 misexpression, obviating the need for intensive clinical follow-up. CONCLUSIONS: This study highlights the importance of TAD boundaries and chromatin interactions in determining the functional impact of copy number variants and provides proof-of-concept for using 4C/HiC-seq as a clinical tool to acquire crucial information for genetic counseling and to support clinical decision-making in cases of suspected TADopathies.


Subject(s)
Chromatin , Receptors, G-Protein-Coupled , Humans , Receptors, G-Protein-Coupled/genetics , Chromatin/genetics , Chromatin/metabolism , Female , Male , Gene Duplication , Chromosome Duplication , Chromosomes, Human, X/genetics , Pedigree
2.
Am J Obstet Gynecol ; 230(3): 368.e1-368.e12, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37717890

ABSTRACT

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.


Subject(s)
DiGeorge Syndrome , Heart Defects, Congenital , Infant , Infant, Newborn , Pregnancy , Female , Humans , Male , DiGeorge Syndrome/diagnosis , DiGeorge Syndrome/genetics , Retrospective Studies , Prenatal Diagnosis , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/genetics , Prenatal Care
3.
Article in English | MEDLINE | ID: mdl-32973963

ABSTRACT

BACKGROUND: Individuals who have colorectal or endometrial cancers displaying loss of immunohistochemical staining of one or more mismatch repair proteins without an identifiable causative germline pathogenic variant have unexplained mismatch repair deficiency (UMMRD). Comprehensive germline genetic testing for Lynch syndrome (LS) includes sequencing and deletion/duplication analysis of MLH1, MSH2, MSH6, and PMS2, deletion analysis of EPCAM, and MSH2 inversion analysis. Updated genetic testing to include elements of comprehensive LS testing not previously completed could further clarify LS status in individuals with UMMRD, allowing for tailored screening guidelines for affected individuals and their family members. However, patient understanding of the potential impact of updated genetic testing for LS is unclear. This study aimed to evaluate the interest in and perceived impact of updated genetic testing among individuals with UMMRD at a tertiary academic center. METHODS: A survey evaluating interest in and perceived impact of updated genetic testing was mailed to 98 potential participants. Electronic health record review was completed for all individuals meeting eligibility criteria. Thirty-one individuals responded to the survey. RESULTS: Results indicate this population is highly interested in updated genetic testing with the perceived impact being primarily for family members to have appropriate genetic testing and screening. Electronic health record review indicates that clinicians have an evolving understanding of causes of UMMRD, representing a potential change in assessment of cancer risk. CONCLUSIONS: Updated risk assessment and genetic counseling with a discussion of the benefits and limitations of germline and somatic genetic testing, is essential as the understanding of UMMRD and genetic testing recommendations for this population evolve.

4.
Leuk Lymphoma ; 60(12): 3020-3027, 2019 12.
Article in English | MEDLINE | ID: mdl-31274040

ABSTRACT

Multiple genes have been identified to cause hereditary predispositions to hematologic malignancies, and characterized by an increased risk to develop myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and/or aplastic anemia (AA). Referral algorithms for patients who may be at higher risk have been proposed, with limited data regarding applicability. Our study aimed to evaluate referral criteria on a population of MDS/AML/AA patients. Demographic information and medical history were obtained from 608 patients referred over a 9-month period. Median age at diagnosis was 67 years (56-73), 387 (64%) were male, and the majority of individuals (54.9%) had AML. Overall, 406 individuals (66.8%) had insufficient documentation to determine whether certain criteria were met. Two hundred and two (33.2%) individuals met at least one criteria for genetic counseling referral; however, only nine (4.5%) were referred. Increased documentation of personal and family history is necessary to better assess and validate the applicability of these criteria.


Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Aged , Aged, 80 and over , Algorithms , Clinical Decision-Making , Disease Management , Female , Genetic Association Studies/methods , Genetic Counseling , Genetic Testing , Humans , Male , Middle Aged , Risk Assessment , Risk Factors
5.
J Genet Couns ; 27(4): 761-769, 2018 08.
Article in English | MEDLINE | ID: mdl-29260485

ABSTRACT

Variant interpretation is a complex process, and classification may vary between sources. This study aimed to determine the practice of cancer genetic counselors regarding discrepancies in variant interpretation and to identify concerns when counseling these discrepancies. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. The vast majority of counselors (93%) had seen a variant interpretation discrepancy in practice. A large majority (96%) of respondents indicated that they conducted their own research on reported variants. Most respondents cited variant databases as the most common resource utilized in researching variants. Approximately 33% of counselors spent 45 min or more of extra time researching a discrepancy compared to researching a variant with a single classification. When asked how they approached counseling sessions involving variant interpretation discrepancies, the free responses emphasized that counselors considered family history, clinical information, and psychosocial concerns, showing that genetic counselors tailored the session to each individual. Discrepancies in variant interpretation are an ongoing concern for clinical cancer genetic counselors, as demonstrated by the fact that counselors desired further resources to aid in addressing these discrepancies, including a centralized database (89%), guidelines from a major organization (88%), continuing education about the issue (74%), and functional studies (58%). Additionally, most respondents reported that the ideal database would be owned by a non-profit organization (59%) and obtain information directly from laboratories (91%). This investigation was the first to address these discrepancies from a clinical point of view. The study demonstrates that discrepancies in variant interpretation are a concern for clinical cancer genetic counselors and outlines the need for additional support.


Subject(s)
Genetic Predisposition to Disease , Neoplasms/genetics , Counselors , Female , Genetic Counseling/statistics & numerical data , Humans , Surveys and Questionnaires
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