SETTING EXPECTATIONS FOR COUPLES UNDERGOING PREIMPLANTATION GENETIC TESTING (PGT) FOR TWO SEPARATE INHERITED SINGLE GENE DISORDERS WITH CONCURRENT 24 CHROMOSOME ANEUPLOIDY SCREENING

Abstract

Outcomes of in vitro fertilization (IVF) cycles with preimplantation genetic testing for monogenic/single gene disorders (PGT-M) and aneuploidy (PGT-A) are well documented (Gutierrez-Mateo, 2009; Konstantinidis M, 2015). With increased availability and expansion of preconception genetic testing, PGT-M is now being requested for multiple single gene conditions. However, there is little information available regarding cycle outcomes and likelihood of obtaining unaffected and euploid embryo(s) for transfer after undergoing PGT-M for two single gene disorders with PGT-A. To report the rates of unaffected and euploid embryo results for patients undergoing PGT-M for two single gene disorders with concurrent PGT-A. Retrospective analysis of trophectoderm (TE) biopsy results from IVF patients who were referred for PGT-M for two disorders with PGT-A. The TE biopsies were performed according to each clinic’s standard procedures. Samples were shipped to a single reference laboratory for genotyping using Illumina Cyto12 SNP-based microarray and an informatics technique (Johnson, 2010). Twenty-seven couples underwent 48 IVF cycles for PGT-M for two single gene disorders and PGT-A. A total of 303 biopsy sample were tested with an average of 6.3 embryos tested per cycle (range 1-17). PGT-M testing was performed for 38 single gene disorders. Of the 27 couples, 12 (44.4%) had both conditions identified due to personal and/or family history of an affected individual, 10 (37.0%) had one condition identified by personal/family history and the other condition detected by genetic carrier screening, and 5 (18.5%) had both conditions identified by genetic carrier screening. The average maternal age for the patient cohort was 33.8 years (range 25–39 years). Seventeen couples (63.0%) had at least one euploid and unaffected (for both single gene conditions) embryo available to transfer after a single IVF cycle. Seven couples (25.9%) pursued additional IVF cycles, six of which eventually had at least one euploid and unaffected embryo identified for transfer. For these couples, an average of 2.5 IVF cycles was necessary (range 2-5 IVF cycles).Table 1Conditions for which PGT-M test development was requested by caseDisorder 1Disorder 1 identified byDisorder 2Disorder 2 identified by2p11.2 duplicationPersonal/family historyCOL6A2 VUS*Personal/family historyATRX-related disorder VUS*Personal/family history18q22.1 microduplicationPersonal/family historyBRCA1-related breast and ovarian cancerPersonal/family historyCombined oxidative phosphorylation deficiency-31Personal/family historyBRCA1-related breast and ovarian cancerCarrier screeningNBN-related cancer susceptibilityCarrier screeningBRCA1-related breast and ovarian cancerCarrier screeningCDH1-related hereditary diffuse gastric cancerCarrier screeningBRCA1-related breast and ovarian cancerPersonal/family historyFabry diseaseCarrier screeningBRCA1-related breast and ovarian cancerPersonal/family historyFragile X syndromeCarrier screeningBRCA1-related breast and ovarian cancerPersonal/family historyCystic fibrosisCarrier screeningBRCA2-related breast and ovarian cancerPersonal/family historyvon Hippel-Lindau syndromePersonal/family historyBRCA2-related breast and ovarian cancerPersonal/family historyGlucose-6-phosphate dehydrogenase (G6PD) deficiencyCarrier screeningBRCA2-related breast and ovarian cancerPersonal/family historyFamilial Mediterranean feverCarrier screeningCDH1-related hereditary diffuse gastric cancerPersonal/family historyPRKAG2-related Wolf Parkinson White syndrome/hypertrophic cardiomyopathyPersonal/family historyCharcot-Marie-Tooth neuropathy, type X1Personal/family historyAlport syndromePersonal/family historyCystic fibrosisCarrier screeningHuntington disease (non-disclosure)Personal/family historyCystinosisPersonal/family historyFragile X syndromePersonal/family historyFamilial Mediterranean feverPersonal/family historyAnkylosing spondylitis (HLA B27)Personal/family historyFamilial Mediterranean feverCarrier screeningL1CAM syndromePersonal/family historyGJB2-related non-syndromic hearing lossCarrier screeningSmith-Lemli-Opitz syndromeCarrier screeningGJB2-related non-syndromic hearing lossCarrier screening21-hydroxylase-deficient congenital adrenal hyperplasiaCarrier screeningHolt-Oram syndromePersonal/family historyFactor XI deficiencyCarrier screeningInclusion body myopathy 2Carrier screeningBiotinidase deficiencyCarrier screeningPolycystic kidney disease VUS*Personal/family historyLong-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)Carrier screeningPRRT2-related disorderPersonal/family historySCN2A-related benign familial neonatal infantile seizures VUS*Personal/family historyPTPN11-related disorderPersonal/family historySLC6A1-related disorderPersonal/family historySCN11A-related disorderPersonal/family historyFLNC-related disorderPersonal/family historySpinal muscular atrophyPersonal/family historyFragile X syndromeCarrier screeningTTN-related dilated cardiomyopathyPersonal/family historyAnkylosing spondylitis (HLA B27)Personal/family history*VUS = variant of unknown significance, as categorized by the genetic testing laboratory Open table in a new tab *VUS = variant of unknown significance, as categorized by the genetic testing laboratory In our study, 15/27 (55.6%) of couples had at least one condition detected by carrier screening. This study highlights the importance of carrier screening even in individuals pursuing PGT-M due to a personal and/or family history of a genetic disorder. When undergoing PGT-A and PGT-M for two inherited genetic conditions, a euploid and unaffected embryo may be possible to achieve in a single IVF cycle. Overall, this information may be useful in counseling patients who wish to consider PGT-M for two single gene disorders to set realistic expectations and plan for the potential need for multiple IVF cycles.