Autosomal Recessive Condition Research Articles

Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the PYGM Gene.

McArdle disease is a rare autosomal recessive condition caused by mutations in the PYGM gene. This gene encodes the skeletal muscle isoform of glycogen phosphorylase or myophosphorylase. Patients with McArdle disease have an inability to obtain energy from their muscle glycogen stores, which manifests as a marked exercise intolerance. Nowadays, there is no cure for this disorder and recommendations are intended to prevent and mitigate symptoms. There is great heterogeneity among the pathogenic variants found in the PYGM gene, and there is no obvious correlation between genotypes and phenotypes. Here, we present the generation of the first human iPSC-based skeletal muscle model harbouring the second most frequent mutation in PYGM in the Spanish population: NM_005609.4: c.2392T>C (p.Trp798Arg). To this end, iPSCs derived from a McArdle patient and a healthy control were both successfully differentiated into skeletal muscle cells using a small molecule-based protocol. The created McArdle skeletal muscle model was validated by confirming distinctive biochemical aspects of the disease such as the absence of myophosphorylase, the most typical biochemical feature of these patients. This model will be very valuable for use in future high-throughput pharmacological screenings.

95 Case Report: A Rare Case of Juvenile Hyaline Fibromatosis Presenting with Bilateral Acro-Osteolysis

Abstract Aim We report a rare case of juvenile hyaline fibromatosis (JHF) leading to acro-osteolysis of bilateral hands in a 54-year-old male patient. Method JHF is an autosomal recessive condition resulting from a mutation of the ANTXR2/ CMG2 gene. It results in an accumulation of hyaline amorphous deposits in the skin and other organs. Other cardinal manifestations include gingival hyperplasia, flexion contracture of large joints and lytic lesions of the long bones. This right-handed window cleaner was referred to a specialist hand unit due to the debilitating accumulation of nodular skin lesions on his bilateral hands. X-ray demonstrated apparent osteolysis to multiple distal phalanges of his bilateral hands. The patient was experiencing difficulties with gripping, leading to barriers to completing his activities of daily living and performing competently within his occupation. Results Currently, there is no cure for this condition. Our patient underwent a total of nine operations over 10 years. Key indications for surgery included ulcerations of the hand lesions or optimising functional and aesthetic outcomes. Radiotherapy and chemotherapy were also attempted with limited beneficial results. Conclusions Our case has highlighted that JHF is an important differential to be considered by hand surgeons when presented with acro-osteolysis of the hand. This is a chronic disease that requires a multidisciplinary team approach to addressing both the social and physical manifestations of the disease. The likelihood of multiple operations is high. Therefore, careful stratification of surgical intervention coupled with shared decision-making with the patient throughout this process is fundamental.

Young adults' reasoning for involving a parent in a genomic decision-making research study.

Young adults have increasing genomic testing opportunities; however, little is known about how equipped they feel about making decisions to learn personal genomic information. We conducted qualitative interviews with 19 young adults, ages 18-21 years old, enrolled in a research study where they made decisions about learning personal genomic risk for developing preventable, treatable, and adult-onset conditions and carrier status for autosomal recessive conditions. Participants had the option to include a parent in their study visit and the decision-making process. The goal of this project was to explore young adults' reasons for involving or not involving a parent in the study and to assess young adults' perspectives about parental roles in their healthcare. Nine participants included a parent in the study and ten did not include a parent. Eleven participants received genomic test results before the interview, while eight participants had not yet received their results at the time of the interview. The study team developed a coding guide and coded interview transcripts inductively and deductively using an interpretive descriptive-analytic approach. Logistical issues dominated solo participants' reasons for not involving a parent in the study, whereas those who involved a parent often cited a close relationship with the parent and the parent's previous involvement in the participant's healthcare as reasons for involving them. Both groups of participants described gradually transitioning to independent healthcare decision-making with age and felt their comfort in medical decision-making depends on the severity of and their familiarity with the situation. Participants recommended that future genomic researchers or clinicians give young adults the option to involve a parent or friend as a support person in research or clinical visits. Although young adults may have different journeys toward independent healthcare decision-making, some may benefit from continued parental or peer involvement after reaching the age of legal adulthood.

Kufor-Rakeb syndrome in two Iranian brothers due to different and novel mutations

Kufor-Rakeb Syndrome (KRS) is an uncommon autosomal recessive neurological condition that frequently has clinical symptoms including supranuclear gaze palsy, dementia, and generalized brain atrophy

The Spectrum of Germline Nucleotide Variants in Gastric Cancer Patients in the Kyrgyz Republic.

Gastric cancer is a major challenge in modern oncology due to its high detection rate and prevalence. While sporadic cases make up the majority of gastric cancer, hereditary gastric cancer is caused by germline mutations in several genes linked to different syndromes. Thus, identifying hereditary forms of gastric cancer is considered crucial globally. A survey study using NGS-based analysis was conducted to determine the frequency of different types of hereditary gastric cancer in the yet-unstudied Kyrgyz population. The study cohort included 113 patients with diagnosed gastric cancer from Kyrgyzstan. The age of patients was 57.6 ± 8.9. Next-generation sequencing analysis of genomic DNA was performed using a custom Roche NimbleGen enrichment panel. The results showed that 6.2% (7/113) of the patients had pathogenic or likely pathogenic genetic variants. Additionally, 3.5% (4/113) of the patients carried heterozygous pathogenic/likely pathogenic variants in high penetrance genes, such as TP53, POLD1, RET, and BRCA2. Moreover, 2.7% (3/113) of the patients carried heterozygous mutations in genes linked to autosomal recessive conditions, specifically PALB2, FANCA, and FANCD2. We have not identified any genetic variants in hereditary GC-associated genes: CDH1, STK11, SMAD4, BMPRIA, APC, MLH1, and others. Our study included patients with sporadic features of GC. The use of recognized criteria (NCCN, Gastric Cancer, Version 2.2022) would increase the number of identified genetic variants in hereditary GC-associated genes. Further research is required to determine the clinical relevance of the genetic variants identified in the current study.

Fumarase Deficiency and Its Effect on Infertility: A Case Series.

Fumarase deficiency is an autosomal recessive condition characterized by severe neurologic abnormalities due to homozygous mutations in the fumarate hydratase (FH) gene. Heterozygous carriers of FH mutations have increased risk of developing uterine fibroids that can be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). The association between FH mutations and infertility remains uncertain. The objective of our study was to characterize the infertility diagnoses, treatments, and outcomes in women presenting to a fertility center who were found to be carriers of fumarase deficiency based on the presence of heterozygous FH mutations. A retrospective case series was conducted including 10 women presenting to an academic fertility center who were found to be FH carriers based on genetic carrier screening. Of the 9 women who were engaged in further workup, 2 had imaging results consistent with uterine fibroids. One woman underwent hysteroscopic myomectomy prior to two courses of ovulation induction with timed intercourse (OI/TIC) followed by one successful cycle of IVF. Of the remaining patients, only 1 woman successfully delivered after a cycle of ovulation induction with intrauterine insemination (OI/IUI). Other patients pursuing OI/IUI, OI/TIC, or monitored natural cycles had unsuccessful experiences. Patients with infertility who are offered genetic testing should be screened for FH mutations, as the carriers are at risk of developing HLRCC-associated uterine fibroids, which can influence fertility and pregnancy. Additional research is needed to investigate the impacts of FH mutations on infertility.

Excessive vincristine exposure in a child being treated for acute lymphoblastic leukaemia with underlying Dubin-Johnson syndrome: a case report.

Dubin-Johnson syndrome is a rare benign autosomal recessive condition that causes an isolated increase of conjugated bilirubin in the serum. Impaired biliary excretion is due to mutation in the multiple drug-resistance protein 2 gene (MRP2). We describe the case of a 4-year-old girl being treated for acute lymphoblastic leukaemia who had a history of conjugated hyperbilirubinaemia and persistently elevated bilirubin levels on initiation of chemotherapy. During treatment for leukaemia, she was diagnosed with Dubin-Johnson syndrome for the underlying condition. Following administration of vincristine at the recommended dose of 1.5mg/m2, an abnormally high vincristine exposure was observed (AUC > 200µg/L*h), approximately 3 times higher than previously reported exposures in a comparable clinical setting. Vincristine dose reductions were applied on subsequent cycles of treatment and resulted in markedly reduced drug exposures, within the normal target range. This case provided a rare opportunity to assess the impact of MRP2 mutations associated with Dubin-Johnson syndrome on the pharmacokinetics of vincristine and strongly indicates that a marked dose reduction should be recommended. Clinicians should be made aware of the potential for altered drug disposition for agents such as vincristine in patients with this rare genetic condition.

High prevalence of MUTYH associated polyposis among minority populations in Israel, due to rare founder pathogenic variants.

Autosomal recessive conditions are common in consanguineous populations. Since consanguinity is common in the Israeli Arab population, we evaluated the rate of MUTYH polyposis (MAP) among polyposis patients in this population and studied Pathogenic Variants (PVs) spectrum. We reviewed health records of all Arab and Druze polyposis patients referred for counseling during 2013-2020 who fulfilled the Israeli Genetic Society criteria for MUTYH/APC testing, in a tertiary center in Northern Israel and four additional gastro-genetic clinics in Israel. The Northern cohort included 37 patients from 30 unrelated families; 8(26.6%) carried bi-allelic MUTYH PVs. The major variant p.Glu452del was detected in 6/8 Druze and Muslim families who shared the same haplotype. Other PVs detected in both cohorts included p.Tyr56Ter, p.His57Arg, c.849+3A>C, p.Ala357fs, and p.Tyr151Cys. Among bi-allelic carriers, 88% reported consanguinity, and 100% had positive family history for polyposis or colorectal cancer (CRC). Generally, the age of CRC was 10 years younger than reported in the general MAP population. MAP accounted for 27% of polyposis cases in the Arab population of Northern Israel. PVs spectrum is unique, with high frequency of the founder variant p.Glu452del. Our results may inform the genetic testing strategy in the Israeli Arab population.

Rate of Manifesting Carriers and Other Unexpected Findings on Carrier Screening

(Abstracted from Prenat Diagn 2023;43:117–125) Obstetric care includes many types of assessment of both mother and baby, including screening for genetic conditions. This can be done through genetic tests referred to as carrier screening, which detect carriers at risk to have children with autosomal recessive and X-linked recessive conditions.

34-year-old female with acute onset quadriparesis and recurrent carpopedal spasm

Gitelman syndrome is an autosomal recessive condition also characterized by hypokalemic metabolic alkalosis, with hypocalciuria and hypomagnesemia

ENPP1 homozygous stop-loss variant causing generalized arterial calcifications of infancy: About a severe neonatal clinical case

Generalized Arterial Calcifications of Infancy (GACI) is an extremely rare autosomal recessive genetic condition, mostly due to pathogenic variations in the ENPP1 gene (GACI1, MIM #208000, ENPP1, MIM #173335). To date 46 likely pathogenic or pathogenic distinct variations in ENPP1 have been described, including nonsense, frameshift, missense, splicing variations, and large deletions. Here we report a case of GACI in a male newborn with a homozygous stop-loss variant in ENPP1 treated in Nancy Regional University Maternity Hospital. Based on proband main clinical signs, clinical exome sequencing was performed and showed a deletion of one nucleotide leading to frameshift and stop-loss (NM_006208.3 (ENPP1):c.2746del,p.(Thr916Hisfs*23)). Clinical presentation is characterized by primary neonatal arterial hypertension resulting in hypertrophic cardiomyopathy decompensated by three cardiogenic shocks and a neonatal deep right sylvian stroke. The child died at 24 days of life.This is the first report of a pathogenic stop-loss variant in ENPP1. It is an opportunity to remind clinicians of GACI disease, a rare and severe etiology in neonates with severe hypertension, and possibility of bisphosphonates therapy.

P-034 Clinical experience with expanded carrier screening results on a sperm donor applicant population

Abstract Study question What is the frequency of clinically significant results from expanded carrier screening (ECS) in a sperm donor applicant population and how should these be managed? Summary answer ECS results revealed clinically significant information for approximately 1 in 51 donor applicants, which warrant specific management considerations in the context of third-party reproduction. What is known already The American Society of Reproductive Medicine (ASRM) Practice Committee published guidance in January 2021 that outlines the recommended carrier screening approach for gamete donors. However, there is no additional direction related to results management including donor suitability, counseling, and informed consent. Prior studies have illustrated the high frequency of donors who are identified as carriers of one or more recessive disorders on an ECS panel; thus, excluding all prospective gamete donors identified as carriers for recessive conditions is not feasible or appropriate given the availability of reciprocal screening for the reproductive partner. Study design, size, duration A retrospective review of donor genetic screening records from July 2017 to December 2021 was performed. Relevant data was extracted and categorized by carrier screening result. Genetic counselors evaluated the health and reproductive risks to the potential donors (PDs) associated with being a carrier of a pathogenic mutation in each gene using published data, reference laboratory interpretations, and the professional health management guidelines. Participants/materials, setting, methods ECS was performed on sperm donor applicants as part of the routine donor qualification process. Testing was performed at an outside reference laboratory after participants provided written consent for genetic testing. The genes included on the ECS panel were analyzed using multiple methodologies. Specific methodologies varied based upon laboratory offerings at the time in which the potential donor entered the donor program. Main results and the role of chance A total of 966 PDs had ECS during the specified timeframe. Of these applicants, 19 total PDs (1.97%) were identified as having potentially significant health risks based on their ECS results. Of those 19 PDs, eleven were found to be either heterozygous or hemizygous for conditions that may convey significant health risks to carriers. Of these, nine were positive for a variant in a gene typically associated with an AR condition and two carried variants in genes associated with X-linked conditions. Eight additional PDs were found to be either compound heterozygous or homozygous for variants in a gene associated with an autosomal recessive condition. Limitations, reasons for caution Donor recruitment was limited to select major metropolitan areas in the U.S.; thus, donor applicants may not represent all ethnic groups or socioeconomic backgrounds. Additionally, this study described results from a single reference laboratory and does not illustrate the variation in ECS panels across genetic testing laboratories. Wider implications of the findings While this study examined ECS results in a donor applicant population, findings are also applicable to the general reproductive population and illustrate the necessity of informed consent and post-test counseling. In some cases, ECS may provide insight on potential future health risks and health management opportunities. Trial registration number Not applicable

Severe congenital neutropenia due to G6PC3 deficiency: early and delayed phenotype of a patient

BackgroundSevere Congenital Neutropenia type 4 (SCN4), is a rare autosomal recessive condition, due to mutations in the G6PC3 gene. The phenotype comprises neutropenia of variable severity and accompanying anomalies.Case presentationWe report a male patient with confirmed G6PC3 deficiency presented with recurrent bacterial infections and multi-systemic complications. Our case was the first with a novel homozygous frameshift mutation in G6PC3. The patient demonstrated large platelets on his peripheral blood smear which is a rare presentation of this disease.ConclusionAs SCN4 patients could be easily missed, it is recommended to consider G6PC3 mutation for any case of congenital, unexplained neutropenia.

The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes.

DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 genome editing in mice to recreate a human missense variant identified in patients with mild PCD and a second, frameshift-null deletion in Dnaaf5. Litters with Dnaaf5 heteroallelic variants showed distinct missense and null gene dosage effects. Homozygosity for the null Dnaaf5 alleles was embryonic lethal. Compound heterozygous animals with the missense and null alleles showed severe disease manifesting as hydrocephalus and early lethality. However, animals homozygous for the missense mutation had improved survival, with partially preserved cilia function and motor assembly observed by ultrastructure analysis. Notably, the same variant alleles exhibited divergent cilia function across different multiciliated tissues. Proteomic analysis of isolated airway cilia from mutant mice revealed reduction in some axonemal regulatory and structural proteins not previously reported in DNAAF5 variants. Transcriptional analysis of mouse and human mutant cells showed increased expression of genes coding for axonemal proteins. These findings suggest allele-specific and tissue-specific molecular requirements for cilia motor assembly that may affect disease phenotypes and clinical trajectory in motile ciliopathies.

Paediatric survivors beyond infancy with Stüve-Wiedemann syndrome – A case series from the West Midlands, UK

Stüve-Wiedemann Syndrome (STWS) is an autosomal recessive condition caused by variants in the LIFR gene, presenting with respiratory failure, hyperthermia and skeletal dysplasia in the neonatal period. Historically identified as a lethal condition, more children are now managed holistically from early in life with multidisciplinary team involvement with improved outcomes. This stems from early diagnosis, supported by molecular testing in the pre and postnatal periods.This report includes five such cases with survival in childhood to 10 years old in the UK affected by skeletal abnormalities, hyperthermia, respiratory distress and their diagnostic odyssey. All cases have a molecular diagnosis; two patients (family 1) were found to be homozygous for a novel pathogenic LIFR variant NM_002310.5:c.704G > A, p.(Trp235Ter). One patient (family 2) is compound heterozygous with the previously reported LIFR variant NM_002310.5:c.756dup p.(Lys253Ter), and a second novel variant NM_002310.5:c.397+5G > A. Two patients (family 3) are homozygous for one of the same LIFR variants NM_002310.5:c.756dup p.(Lys253Ter) as in family 2.This report discusses genotypic and phenotypic data for five patients with STWS, as well as the need for multi-disciplinary, proactive management and genetic counselling.

Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME): three new cases and review of the mutational spectrum

BackgroundSpinal muscular atrophy (SMA) could be classified as 5q and non-5q, based on the chromosomal location of causative genes. A rare form of non-5q SMA is an autosomal-recessive condition called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by myoclonic and generalized seizures with progressive neurological deterioration. SMA-PME is a clinically heterogeneous disorder that arises from biallelic pathogenic variants in ASAH1 gene.MethodsFollowing clinical and primary laboratory assessments, whole-exome sequencing was performed to detect the disease-causing variants in three cases of SMA-PME from different families. Also, Multiplex ligation-dependent probe amplification (MLPA) was employed for determining the copy numbers of SMN1 and SMN2 genes to rule out 5q SMA.ResultsExome sequencing revealed two different homozygous missense mutations (c.109 C > A [p.Pro37Thr] or c.125 C > T [p.Thr42Met]) in exon 2 of the ASAH1 gene in the affected members of the families. Sanger sequencing of the other family members showed the expected heterozygous carriers. In addition, no clinically relevant variant was identified in patients by MLPA.ConclusionThis study describes two different ASAH1 mutations and the clinical picture of 3 SMA-PME patients. In addition, previously reported mutations have been reviewed. This study could help to fortify the database of this rare disease with more clinical and genomic data.

Only one beer can be mortal: a case report of two sisters with cardiac arrest due to a homozygous mutation in PPA2 gene

We report the long way to the correct diagnosis in two teenage sisters who developed a cardiac arrest after consuming minimal amounts of alcohol. The older girl dramatically survived two cardiac arrests at the age of 14 and 15 years. She underwent an extensive examination that revealed isolated cardiac abnormalities including fibrosis, dilated cardiomyopathy and inflammation. The younger girl also had a cardiac arrest at the age of 15 and died suddenly after consuming 1–2 beers, 3 years after her sister´s first incident. Autopsy of the heart revealed acute myocarditis without structural alterations. Multigene panel analysis (not including PPA2) showed SCN5A and CACNA1D variants in both sisters and their healthy mother. Six years later duo exome allowed the diagnosis of an autosomal recessive PPA2-related mitochondriopathy. We discuss the molecular results and clinical picture of our patients compared to other PPA2-related cases. We highlight the diagnostic contribution of multigene panels and exome analysis. The genetic diagnosis is important for medical care and for everyday life, specifically because alcohol intake can result in cardiac arrest and should be strictly avoided. Conclusion: Duo exome sequencing clarified the diagnosis of PPA2-related mitochondriopathy in two sisters with isolated cardiac features and sudden cardiac arrest triggered by minimal amounts of alcohol.What is Known:• Multigene-Panel or exome analysis is a valuable tool to identify genetic causes of hereditary cardiac arrhythmias.• Variants of unknown significance can lead to misinterpretation. PPA2-related mitochondriopathy is a very rare autosomal recessive condition that is normally fatal in infancy.What is New:• Duo exome analysis in two teeenage sisters with cardiac arrest revealed a homozygous mild PPA2 mutation as the underlying pathology restricted to the heart muscle

Implementation of universal pan-cancer germline genetic testing in an Arab population: The jordanian exploratory cancer fenetics (Jo-ECAG) study.

10591 Background: Germline genetic testing (GGT) has a significant impact on cancer care. While universal testing has been selectively implemented in the U.S., less is known about adoption of this approach in other ethnic groups. This study reports on GGT results among newly diagnosed cancer patients (pts) in Jordan. Methods: Jo-ECAG was a prospective study of newly diagnosed cancer pts between April 2021 and September 2022 who underwent 84 gene GGT. Patients were classified based on the 2020 National Comprehensive Cancer Network (NCCN) GGT criteria as meeting (in criteria, IC) or not meeting criteria (out of criteria, OOC). Demographics and clinical history were clinician-provided. Pts who were carriers for autosomal recessive conditions were excluded from pathogenic germline variant (PGV) count. Differences in proportions were determined using two-tailed Fisher’s exact test and the significance was set at p≤ 0.05. Results: The cohort consisted of 3,313 Arabic cancer pts, predominantly female (69.8%), with a median age of 54 at testing. Breast was the most commonly diagnosed cancer (50.4%), followed by colorectal (14.9%) and prostate (14.3%). 52% of pts tested were guidelines-based (IC). 460 PGVs were identified in 426 (12.9%) pts. PGVs were most commonly identified in APC (predominantly I1307K variant, 144 pts, 4.4%), BRCA2 (72, 2.2%), BRCA1 (36, 1.1%), CHEK2 (26, 0.8%) and ATM (25, 0.8%). While IC pts were more likely than OOC pts to have a PGV (15.7% vs 9.8%, p<0.0001), 156 (36.6%) pts with PGVs were OOC. 232 (54.5%) pts had PGVs in DNA damage response and repair/homologous recombination repair (DDR/HRR) genes, including 61 (26.3%) OOC pts. 3,602 variants of uncertain significance (VUS) were identified in 2,199 (66.4%) pts with 1,868 of these pts having only VUS results (56.4%), but the frequency in the latter group was not different between IC and OOC pts (p=0.42). Conclusions: Universal GGT of all new cancer pts was successfully implemented and led to actionable findings that would have been missed with guidelines-based testing. With the exception of an overrepresentation of APC I1307K variants, PGV rates were similar to Western ethnic groups. Over half of pts had PGVs in DDR/HRR genes that confer potential eligibility for targeted therapies and/or clinical trials. While VUS rates were high, they were similar between IC and OOC pts. Additional efforts to sequence underrepresented populations and develop variant interpretation methods agnostic to ancestry may help to mitigate these disparities.

Scalable new model of genomic care delivery: Assessing psychological outcomes.

10600 Background: Germline testing (GT) use is on the rise given testing implications for identifying cancer susceptibility and therapeutically actionable alterations. Scalable models of care that emphasize post-test, as opposed to pre-test, genetic counseling are needed to meet demand. However, little is known about the psychological impact (PI) of test result disclosure in such models. Methods: The enterprise-wide City of Hope INSPIRE study offers all consented patients GT for cancer susceptibility (155 genes) and actionable disorders (59 genes). In 2022, we surveyed a sub-set of English-speaking participants ~1 month following test result disclosure. We evaluated PI using the Feelings about Genomic Testing Results (FACToR) measure (distress/ uncertainty subscales 0-12; positive subscale 0-16) and explored associations between patient characteristics, GT results and PI. Results: Of 1000 patients surveyed, 615 completed at least one of the FACToR questions. Participants were mostly white (n=463, 75%) or Asian (n=12.52, 13%) and female (n=419, 68%) with a mean age of 62 yrs. 357 (61%) had a cancer diagnosis and most opted for both GT panels (97%). Eighteen percent had a pathogenic/likely pathogenic variant (PV/LPV) in an autosomal dominant condition, 8% were carriers for an autosomal recessive condition, 53% had at least one variant of unknown significance (VUS) and 21% had negative results. Most patients (n=583, 95%) had low levels of distress with a mean score of 1.67 (SD 2.31). Out of the 30 (5%) patients with higher levels of distress (score >7), results were similar for patients with and without cancer (5% and 4% respectively). Of the 30 patients with higher distress, 67% had a P/LPV variant (13 with and 7 without cancer). Patients also had low levels of uncertainty with a mean score of 2.22 (SD 2.61) and 93% (n=569) scored <7. For those who scored higher on uncertainty (n=44, 7%), most people had cancer and a VUS (n=16, 36%), followed by cancer and LPV/PV (n=10, 23%) followed by patient without cancer with a VUS (n=6, 14%). Finally, 56% (n=44) had high positivity scores (9-16); mean 9.18 (SD 4.31). Fifty-six percent of patients felt a “good/great deal” happy about their GT and 54% were a good/great deal relieved about their results. Conclusions: After implementing an enterprise-wide germline testing program with an emphasis on robust post-test genetic counseling, we found very little evidence of post-disclosure distress or uncertainty. Similar to prior studies, we found that a small proportion of patients may be more vulnerable to negative PI. More work is needed to prospectively identify at risk patients to provide support to this population as we continue to develop safe, effective, and scalable models of care.

The utility of multiple genomic technologies for interpretation of modern next generation sequencing: A novel case of three FANCA gene variants resulting in autosomal recessive Fanconi anaemia

Fanconi anaemia (FA) is a rare autosomal recessive condition resulting in changes in the FANC gene family. This report describes a case of Fanconi anaemia in a family with complex biallelic variants. The patient is a 32-year-old female diagnosed with FA on cascade testing during childhood with chromosome breakage studies. On examination she had a fixed deformity of the right thumb and the proximal interphalangeal joint was immobile. Her brother shared this radial abnormality and had FA, requiring a bone marrow transplant. She presented in adulthood seeking further BRCA advice and had next generation sequencing that showed three variants in the FANCA gene. One allele a known pathogenic change, the other had two sequence variants in tandem that have been reported as variants of uncertain significance. There is one other unrelated case of these two variants occurring together in cis, resulting in Fanconi anaemia. This case is an interesting example of three variants in the FANCA gene, one allele with a pathogenic deletion and the other with a single complex allele made up of two missense variants of uncertain significance, likely manifesting with FA. It highlights the utility of different genetic technologies in the interpretation of next generation sequencing.