Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions

PurposeThe purpose of this study was to evaluate the clinical performance of carrier screening for cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy with reflex single-gene noninvasive prenatal screening (sgNIPS), which does not require paternal carrier screening.MethodsAn unselected sample of 9151 pregnant individuals from the general US pregnant population was screened for carrier status, of which 1669 (18.2%) were identified as heterozygous for one or more pathogenic variants and reflexed to sgNIPS. sgNIPS results were compared with newborn outcomes obtained from parent survey responses or provider reports for a cohort of 201 pregnancies.ResultsOverall, 98.7% of pregnant individuals received an informative result (no-call rate = 1.3%), either a negative carrier report or, if identified as heterozygous for a pathogenic variant, a reflex sgNIPS report. In the outcomes cohort, the negative predictive value of sgNIPS was 99.4% (95% CI = 96.0%-99.9%) and average positive predictive value (PPV) of sgNIPS was 48.3% (95% CI = 36.1%-60.1%). Importantly, personalized PPVs accurately reflected the percentage of affected pregnancies in each PPV range, and all pregnancies with a sgNIPS fetal risk of >9 in 10 (90% PPV) were affected.ConclusionAlthough traditional carrier screening is most effective when used to assess reproductive risk before pregnancy, more than 95% of the time it is pursued during a pregnancy and is complicated by incomplete uptake of paternal carrier screening (<50%) and misattributed paternity (～10%). Even in an idealized setting, when both partners have carrier screening, the maximum risk for having an affected pregnancy is 1 in 4 (equivalent of a 25% PPV). Carrier screening with sgNIPS during pregnancy is an alternative that does not require a paternal sample and provides accurate fetal risk in a timely manner that can be used for prenatal counseling and pregnancy management.     

Comparing ethnicity-based and expanded carrier screening methods at a single fertility center reveals significant differences in carrier rates and carrier couple rates

PurposeTo evaluate the efficiency of expanded carrier screening (ECS) compared with ethnicity-based screening in identifying carriers.MethodsA total of 4232 infertility patients underwent ECS from a single genetic testing laboratory at our center between June 2013 and July 2015. Self-reported ethnicity was recorded. Carrier rates based on ECS were calculated. In addition, carrier status was determined for two other screening panels: ethnicity-based guidelines or the ECS panel recommended by the American College of Obstetricians and Gynecologists (ACOG) using ECS results. Carrier rate and carrier couple rates were compared in the overall study population and in each self-reported ethnicity.ResultsThe ECS panel used to screen the patient population identified 1243 carriers (29.4%). For the same population, ethnicity-based screening and the ACOG panel would have identified 359 (8.5%) and 659 carriers (15.6%), respectively, representing statistically significant differences. Differences in identifying carriers across self-reported ethnicities varied. In 15 couples (1.2%), both partners carried pathogenic variants for the same genes, 47% of whom would have been missed had screening been ethnicity-based.ConclusionWe propose that all reproductive-aged women should be offered ECS. Carrier couple rates would likely increase further with expansion of the panel, playing a pivotal role in preventing genetic disease in fertility clinics.     

Couple-based expanded carrier screening provided by general practitioners to couples in the Dutch general population: psychological outcomes and reproductive intentions

PurposeThe aim of expanded preconception carrier screening (ECS) is to inform any couple wishing to conceive about their chances of having children with severe autosomal or X-linked recessive conditions. Responsible implementation of ECS as reproductive genetic screening in routine care requires assessment of benefits and harms. We examined the psychological outcomes of couple-based ECS for 50 autosomal recessive (AR) conditions provided by general practitioners (GPs) to couples from the Dutch general population.MethodsDutch GPs invited 4,295 women aged 18–40. We examined anxiety (State-Trait Anxiety Inventory, STAI-6), worry, decisional conflict (DCS) over time in participants declining GP counseling or attending GP counseling with/without testing.ResultsOne hundred ninety couples participated; 130 attended counseling, of whom 117 proceeded with testing. No carrier couples were identified. Before counseling, worry (median 6.0) and anxiety (mean 30–34) were low and lower than the population reference (36.4), although some individuals reported increased anxiety or worry. At follow-up, test acceptors reported less anxiety than test decliners (mean 29 vs. 35); differences in anxiety after testing compared to before counseling were not meaningful. Most participants (90%) were satisfied with their decision (not) to undergo testing.ConclusionSome individuals reported temporarily clinically relevant distress. Overall, the psychological outcomes are acceptable and no barrier to population-wide implementation.     

Carrier screening in the Mexican Jewish community using a pan-ethnic expanded carrier screening NGS panel

PurposeThe Mexican Jewish community (MJC) is a previously uncharacterized, genetically isolated group composed of Ashkenazi and Sephardi-Mizrahi Jews who migrated in the early 1900s. We aimed to determine the heterozygote frequency of disease-causing variants in 302 genes in this population.MethodsWe conducted a cross-sectional study of the MJC involving individuals representing Ashkenazi Jews, Sephardi-Mizrahi Jews, or mixed-ancestry Jews. We offered saliva-based preconception pan-ethnic expanded carrier screening, which examined 302 genes. We analyzed heterozygote frequencies of pathogenic/likely pathogenic variants and compared them with those in the Genome Aggregation Database (gnomAD).ResultsWe recruited 208 participants. The carrier screening results showed that 72.1% were heterozygous for at least 1 severe disease-causing variant in 1 of the genes analyzed. The most common genes with severe disease-causing variants were CFTR (16.8% of participants), MEFV (11.5%), WNT10A (6.7%), and GBA (6.7%). The allele frequencies were compared with those in the gnomAD; 85% of variant frequencies were statistically different from those found in gnomAD (P <.05). Finally, 6% of couples were at risk of having a child with a severe disorder.ConclusionThe heterozygote frequency of at least 1 severe disease-causing variant in the MJC was 72.1%. The use of carrier screening in the MJC and other understudied populations could help parents make more informed decisions.     

Incidental molecular diagnoses and heterozygous risk alleles in a carrier screening cohort

PurposeExpanded pan-ethnic carrier screening is an effective tool for the management of reproductive risk. However, growth in the number of conditions screened, in combination with increasingly more comprehensive test methodologies, can lead to the detection of genetic findings that may affect the health of the tested individual. The objective of this study was to investigate the frequency of pathogenic genotypes in a presumed healthy carrier screening cohort to facilitate broader discussions regarding disclosure of genetic information from carrier screening.MethodsA retrospective analysis of 73,755 targeted carrier screens was performed to identify individuals with pathogenic genotypes and heterozygous risk alleles.ResultsIn this study, we identified 79 individuals (0.11%) with pathogenic genotypes associated with moderate to profound autosomal recessive or X-linked conditions. In addition, 10 cases had chromosome X dosage abnormalities suggestive of a sex chromosome abnormality. Heterozygote risk alleles represented the majority of ancillary findings in this cohort, including 280 female carriers of FMR1 premutation alleles, 15 heterozygous females with pathogenic DMD variants, and 174 heterozygotes with pathogenic variants in genes that may confer increased risk for somatic malignancies in the heterozygous state.ConclusionThese data suggest that nearly 1% of individuals undergoing carrier screening will have a finding that may require clinical evaluation or surveillance.     

The dangers of including nonclassical cystic fibrosis variants in population-based screening panels: p.L997F,further genotype/phenotype correlation data

PurposeRecently, a major CLIA-certified commercial laboratory began offering an extended cystic fibrosis (CF) carrier screening panel containing 103 variants including p.L997F. Our laboratory has already received two invasive prenatal diagnostic samples where one parent carries a classic CF mutation and the other carries p.L997F. One fetus inherited both variants.MethodsWe queried our databases containing >2500 CF sequencing analyses to find all individuals with the p.L997F variant. For all compound heterozygous patients, clinical information was obtained by a genetic counselor telephoning the medical provider.ResultsThere were four compound heterozygous patients carrying the p.L997F variant and a second pathogenic CF allele. Three patients were discovered by newborn screening and were asymptomatic at ages 28, 40, and 60 months, respectively. The fourth individual is currently aged 10 years and has the diagnosis of atypical CF with recurrent pancreatitis, sinusitis with nasal polyps, and mild lung disease. His length and weight are in the 90th and 75th centile, respectively. The fifth patient was a compound heterozygote for p.F508del and a complex allele containing p.L997F and a deletion of exons 2–9. This patient has the diagnosis of classical CF.ConclusionThe p.L997F variant is not a classical CF mutation, and its inclusion in population-based carrier screening panels is a disservice to couples who may make poorly informed reproductive decisions based on incorrect assumptions.     

Expanded carrier screening in an infertile population: how often is clinical decision making affected?

PurposeOptions for preconception genetic screening have grown dramatically. Expanded carrier screening (ECS) now allows for determining carrier status for hundreds of genetic mutations by using a single sample, and some recommend ECS prior to in vitro fertilization. This study seeks to evaluate how often ECS alters clinical management when patients present for infertility care.MethodsAll patients tested with ECS at a single infertility care center from 2011 to 2014 were evaluated. The overall rate of positive ECS results and the number of couples who were carriers of the same genetic disorder were evaluated.ResultsA total of 6,643 individuals were tested, representing 3,738 couples; 1,666 (25.1%) of the individuals had a positive test result for at least one disorder. In 8 of the 3,738 couples, both members of the couple were positive for the same genetic disorder or had a test result that placed them at risk of having an affected child. Three of eight cases were cystic fibrosis. In this cohort, ECS affected clinical care eight times after 6,643 tests (0.12%, confidence interval: 0.05–0.24%) in 3,738 couples (0.21%, confidence interval: 0.09–0.42%).ConclusionsECS is becoming more widespread. In a large case series, ECS affected clinical decision making for patients presenting for infertility care in 0.21% of cases. This information must be weighed when utilizing these tests and may be a helpful part of patient counseling.Genet Med 18 11, 1097–1101.     

A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1Α and HNF1Β genes

BackgroundMaturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now.Case reportA female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant.ConclusionDigenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.     

Inter-lab concordance of variant classifications establishes clinical validity of expanded carrier screening

Expanded carrier screening (ECS) panels that use next-generation sequencing aim to identify pathogenic variants in coding and clinically relevant non-coding regions of hundreds of genes, each associated with a serious recessive condition. ECS has established analytical validity and clinical utility, meaning that variants are accurately identified and pathogenic variants tend to alter patients' clinical management, respectively. However, the clinical validity of ECS, that is, correct discernment of whether an identified variant is indeed pathogenic, has only been shown for single conditions, not for panels. Here, we evaluate the clinical validity of a >170-condition ECS panel by assessing concordance between >12 000 variant interpretations classified with guideline-based criteria to their corresponding per-variant combined classifications in ClinVar. We observe 99% concordance at the level of unique variants. A more clinically relevant frequency-weighted analysis reveals that fewer than 1 in 500 patients are expected to receive a report with a variant that has a discordant classification. Importantly, gene-level concordance is not diminished for rare ECS conditions, suggesting that large panels do not balloon the panel-wide false-positive rate. Finally, because ECS is intended to serve all reproductive-age couples, we show that classification of novel variants is feasible and scales predictably for a large population.     

Genetic ancestry analysis on >93,000 individuals undergoing expanded carrier screening reveals limitations of ethnicity-based medical guidelines

PurposeCarrier status associates strongly with genetic ancestry, yet current carrier screening guidelines recommend testing for a limited set of conditions based on a patient’s self-reported ethnicity. Ethnicity, which can reflect both genetic ancestry and cultural factors (e.g., religion), may be imperfectly known or communicated by patients. We sought to quantitatively assess the efficacy and equity with which ethnicity-based carrier screening captures recessive disease risk.MethodsFor 93,419 individuals undergoing a 96-gene expanded carrier screen (ECS), correspondence was assessed among carrier status, self-reported ethnicity, and a dual-component genetic ancestry (e.g., 75% African/25% European) calculated from sequencing data.ResultsSelf-reported ethnicity was an imperfect indicator of genetic ancestry, with 9% of individuals having >50% genetic ancestry from a lineage inconsistent with self-reported ethnicity. Limitations of self-reported ethnicity led to missed carriers in at-risk populations: for 10 ECS conditions, patients with intermediate genetic ancestry backgrounds—who did not self-report the associated ethnicity—had significantly elevated carrier risk. Finally, for 7 of the 16 conditions included in current screening guidelines, most carriers were not from the population the guideline aimed to serve.ConclusionSubstantial and disproportionate risk for recessive disease is not detected when carrier screening is based on ethnicity, leading to inequitable reproductive care.     

Targeted BRCA1/2 population screening among Ashkenazi Jewish individuals using a web-enabled medical model: An observational cohort study

PurposeThis study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs).MethodsAcross 4 cities in the United States, from December 2017 to March 2020, individuals aged ≥25 years with ≥1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years.ResultsA total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing.ConclusionAlthough continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated.     

Implementing preconception expanded carrier screening in a universal health care system: A model-based cost-effectiveness analysis

PurposeThe limited evidence available on the cost-effectiveness (CE) of expanded carrier screening (ECS) prevents its widespread use in most countries, including Italy. Herein, we aimed to estimate the CE of 3 ECS panels (ie, American College of Medical Genetics and Genomics [ACMG] Tier 1 screening, “Focused Screening,” testing 15 severe, highly penetrant conditions, and ACMG Tier 3 screening) compared with no screening, the health care model currently adopted in Italy.MethodsThe reference population consisted of Italian couples seeking pregnancy with no increased personal/familial genetic risk. The CE model was developed from the perspective of the Italian universal health care system and was based on the following assumptions: 100% sensitivity of investigated screening strategies, 77% intervention rate of at-risk couples (ARCs), and no risk to conceive an affected child by risk-averse couples opting for medical interventions.ResultsThe incremental CE ratios generated by comparing each genetic screening panel with no screening were: −14,875 ± 1,208 €/life years gained (LYG) for ACMG1S, −106,863 ± 2,379 €/LYG for Focused Screening, and −47,277 ± 1,430 €/LYG for ACMG3S. ACMG1S and Focused Screening were dominated by ACMG3S. The parameter uncertainty did not significantly affect the outcome of the analyses.ConclusionFrom a universal health care system perspective, all the 3 ECS panels considered in the study would be more cost-effective than no screening.     

Clinical impact and cost-effectiveness of a 176-condition expanded carrier screen

PurposeCarrier screening identifies couples at high risk for conceiving offspring affected with serious heritable conditions. Minimal guidelines recommend offering testing for cystic fibrosis and spinal muscular atrophy, but expanded carrier screening (ECS) assesses hundreds of conditions simultaneously. Although medical societies consider ECS an acceptable practice, the health economics of ECS remain incompletely characterized.MethodsPreconception screening was modeled using a decision tree comparing minimal screening and a 176-condition ECS panel. Carrier rates from >60,000 patients, primarily with private insurance, informed disease incidence estimates, while cost and life-years-lost data were aggregated from the literature and a cost-of-care database. Model robustness was evaluated using one-way and probabilistic sensitivity analyses.ResultsFor every 100,000 pregnancies, 290 are predicted to be affected by ECS-panel conditions, which, on average, increase mortality by 26 undiscounted life-years and individually incur $1,100,000 in lifetime costs. Relative to minimal screening, preconception ECS reduces the affected birth rate and is estimated to be cost-effective (i.e.,<$50,000 incremental cost per life-year), findings robust to perturbation.ConclusionBased on screened patients predominantly with private coverage, preconception ECS is predicted to reduce the burden of Mendelian disease in a cost-effective manner compared with minimal screening. The data and framework herein may facilitate similar assessments in other cohorts.     

Preconception carrier screening yield: effect of variants of unknown significance in partners of carriers with clinically significant variants

PurposeExpanded preconception carrier screening (ECS) identifies at-risk couples (ARCs) for multiple diseases. ECS reports currently include only pathogenic/likely pathogenic variants (P/LPVs). Variants of unknown significance (VUS) are not reported, unlike genomic or chromosomal array test results in other post/prenatal settings. Couples who are P/LP and VUS carriers (P/LP*VUS) may be at risk, particularly in genes with high P/LP carrier rates. We examined the possible contribution of P/LP*cVUS (coding, nonsynonymous VUS) matings to ECS yield in an Ashkenazi Jewish cohort, a population with well-established preconception screening.MethodsWe analyzed 672 Ashkenazi Jewish genome sequences (225,456 virtual matings) for variants in three different gene sets and calculated the rates of P/LP*P/LP and P/LP*cVUS matings.ResultsAcross 180 genes, we identified 4671 variants: 144 (3.1%) P/LP and 1963 (42%) VUS. Across gene sets, the proportion of P/LP*P/LP and P/LP*cVUS ARCs was 2.7–3.8% and 6.8–7.5%, respectively.ConclusionDisregarding VUS in ECS may miss ARCs. Even if only 10% of couples currently classified as P/LP*cVUS are ultimately reclassified as P/LP*P/LP, ECS yield would increase by ≈20%. While current understanding of VUS precludes VUS reporting in ECS, these findings underscore the importance of VUS reclassification. This will crucially depend on enlarging population frequency databases, especially of affected individuals.     

Population-based genetic testing of asymptomatic women for breast and ovarian cancer susceptibility

PurposeThe identification of carriers of hereditary breast and ovarian cancer (HBOC) gene variants through family cancer history alone is suboptimal, and most population-based genetic testing studies have been limited to founder mutations in high-risk populations. Here, we determine the clinical utility of identifying actionable variants in a healthy cohort of women.MethodsGermline DNA from a subset of healthy Australian women participating in the lifepool project was screened using an 11-gene custom sequencing panel. Women with clinically actionable results were invited to attend a familial cancer clinic (FCC) for post-test genetic counseling and confirmatory testing. Outcomes measured included the prevalence of pathogenic variants, and the uptake rate of genetic counseling, risk reduction surgery, and cascade testing.ResultsThirty-eight of 5908 women (0.64%) carried a clinically actionable pathogenic variant. Forty-two percent of pathogenic variant carriers did not have a first-degree relative with breast or ovarian cancer and 89% pursued referral to an FCC. Forty-six percent (6/13) of eligible women pursued risk reduction surgery, and the uptake rate of cascade testing averaged 3.3 family members per index case.ConclusionWithin our cohort, HBOC genetic testing was well accepted, and the majority of high-risk gene carriers identified would not meet eligibility criteria for genetic testing based on their existing family history.     

A validation of models for prediction of pathogenic variants in mismatch repair genes

PurposeModels used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer.MethodsWe performed a validation study of 4 models, Leiden, MMRpredict, PREMM₅, and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance.ResultsMMRpro with additional tumor information (MMRpro+) and PREMM₅ outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95% CI = 0.89-1.08). The combination models showed improvement over PREMM₅ and performed similar to MMRpro+.ConclusionMMRpro+ and PREMM₅ performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies.     

Experiences and attitudes of hereditary cancer screening patients in a consumer directed testing model

BackgroundSince 2015, the Information is Power initiative has offered free and reduced cost hereditary cancer screening to the North Alabama population with a consumer-initiated model. Patients received pre-test and post-test education through a genetic counseling video. Positive results also received a call from a genetic counselor.ObjectiveWe surveyed past Information is Power patients to assess if video education and electronic result delivery addressed the needs of a hereditary cancer screening population.MethodsAn electronic survey was sent out to Information is Power patients who opted into research contact. The survey assessed participant knowledge, satisfaction with result delivery, and perceived uncertainty after receiving test results.Results213 participants completed the survey. Eighteen percent of participants would have preferred individual communication with a genetics specialist about their results. Over 99 % of survey participants correctly interpreted a positive result, while 73 % correctly interpreted a negative result. Overall, participants were certain about the impact of their genetic test results.Practice ImplicationsThese findings support a model of population genetic testing and genetic counseling that is sustainable while meeting the educational needs of most participants. Observed misconceptions surrounding a negative result should be highlighted in future population screening patient resources to meet patient needs.     

Clinical utility of expanded carrier screening: results-guided actionability and outcomes

PurposeExpanded carrier screening (ECS) informs couples of their risk of having offspring affected by certain genetic conditions. Limited data exists assessing the actions and reproductive outcomes of at-risk couples (ARCs). We describe the impact of ECS on planned and actual pregnancy management in the largest sample of ARCs studied to date.MethodsCouples who elected ECS and were found to be at high risk of having a pregnancy affected by at least one of 176 genetic conditions were invited to complete a survey about their actions and pregnancy management.ResultsThree hundred ninety-one ARCs completed the survey. Among those screened before becoming pregnant, 77% planned or pursued actions to avoid having affected offspring. Among those screened during pregnancy, 37% elected prenatal diagnostic testing (PNDx) for that pregnancy. In subsequent pregnancies that occurred in both the preconception and prenatal screening groups, PNDx was pursued in 29%. The decision to decline PNDx was most frequently based on the fear of procedure-related miscarriage, as well as the belief that termination would not be pursued in the event of a positive diagnosis.ConclusionECS results impacted couples' reproductive decision-making and led to altered pregnancy management that effectively eliminates the risk of having affected offspring.     

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy–like disease

PurposeTo understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.MethodsWe identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.ResultsThe patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient’s urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.ConclusionMitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy–like disease.