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Genetics of Growth Disorders-Which Patients Require Genetic Testing?

ABSTRACT: The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH-IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH-IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH-IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for management of the growth disorder.

SUBMITTER: Argente J

PROVIDER: S-EPMC6742727 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Genetics of Growth Disorders-Which Patients Require Genetic Testing?

Argente Jesús J Tatton-Brown Katrina K Lehwalder Dagmar D Pfäffle Roland R

Frontiers in endocrinology 20190906

The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled <i>Pragmatism</i> vs. <i>Curiosity in Genetic Diagnosis of Growth Disorders</i>, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary ...[more]

PMID: 31555216

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Project description:Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established.A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared.Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients.CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

Project description:BackgroundIn vitro fertilization (IVF) with preimplantation genetic testing (PGT) has markedly improved clinical pregnancy outcomes for carriers of gene mutations or chromosomal structural rearrangements by the selection of embryos free of disease-causing genes and chromosome abnormalities. However, for detecting whole or segmental chromosome aneuploidies, gene variants or balanced chromosome rearrangements in the same embryo require separate procedures, and none of the existing detection platforms is universal for all patients with different genetic disorders.MethodsHere, we report a cost-effective, family-based haplotype phasing approach that can simultaneously evaluate multiple genetic variants, including monogenic disorders, aneuploidy, and balanced chromosome rearrangements in the same embryo with a single test. A total of 12 monogenic diseases carrier couples and either of them carried chromosomal rearrangements were enrolled simultaneously in this present study. Genome-wide genotyping was performed with single-nucleotide polymorphism (SNP)-array, and aneuploidies were analyzed through SNP allele frequency and Log R ratio. Parental haplotypes were phased by an available genotype from a close relative, and the embryonic genome-wide haplotypes were determined through family haplotype linkage analysis (FHLA). Disease-causing genes and chromosomal rearrangements were detected by haplotypes located within the 2 Mb region covering the targeted genes or breakpoint regions.ResultsTwelve blastocysts were thawed, and then transferred into the uterus of female patients. Nine pregnancies had reached the second trimester and five healthy babies have been born. Fetus validation results, performed with the amniotic fluid or umbilical cord blood samples, were consistent with those at the blastocyst stage diagnosed by PGT.ConclusionsWe demonstrate that SNP-based FHLA enables the accurate genetic detection of a wide spectrum of monogenic diseases and chromosome abnormalities in embryos, preventing the transfer of parental genetic abnormalities to the fetus. This method can be implemented as a universal platform for embryo testing in patients with different genetic disorders.

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Genetics of Growth Disorders-Which Patients Require Genetic Testing?

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Genetics of Growth Disorders-Which Patients Require Genetic Testing?

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