Heterozygous Variant Of Uncertain Significance Research Articles

#1854 Prevalence of Fabry disease in chronic hemodialysis patients: a multicenter screening approach

Abstract Background and Aims Fabry disease (FD), an X-linked lysosomal storage disorder caused by alpha-galactosidase A (α-Gal A) deficiency, leads to significant morbidity and early mortality due to progressive organ failure. Given the availability of enzyme replacement therapy, early identification of FD is crucial for improving patient outcomes. Method A multicenter screening was conducted among chronic hemodialysis patients across six centers. We utilized a two-tiered diagnostic approach. Initially, α-Gal A activity was measured from dried blood spots on filter paper. Subsequently, those with reduced enzyme levels underwent GLA gene mutation analysis. Results Out of 428 patients, 255 (102 females and 153 males) were selected for testing, leading to the analysis of 239 patients. In the male cohort, the average α-Gal A activity was 21.84 ± 11.9 µmol/L/h, with 34 males below the cut-off value (<15.3 µmol/L/h) but with normal lyso-Gb3 levels and no mutations. Among females, α-Gal A levels were typically within the normal range. Notably, one female was found to have a heterozygous variant of uncertain significance in the GLA gene [p.(Asp313Tyr)] in exon 6, with normal α-Gal A and lyso-Gb3 levels. Screening of other family members was not possible, as they resided abroad although we recommended it. Conclusion Screening for AFD in high-risk groups, such as hemodialysis patients, is challenging yet essential. Implementing α-Gal A measurement as a standard procedure for newly registered hemodialysis patients could prospectively identify potential Fabry carriers, offering more excellent utility than our cross-sectional study. While identifying index patients at a late disease stage may not benefit the patients themselves, it is crucial for early detection of family members, potentially altering their disease course. This proactive approach, supported by national and international guidelines, could significantly impact the management and outcomes of AFD.

Retinopathy With Variant of Unknown Significance and Atypical Chorioretinal Coloboma in the Setting of Prematurity.

A 37-week-old girl underwent ophthalmic examination. Born at 32 weeks, the infant weighed 680 grams and received high-flow nasal cannula for respiratory distress of the newborn. Dilated fundus examination of the right eye revealed an atypical chorioretinal coloboma; the left eye revealed hyperpigmentary changes in the macula. Fluorescein angiography of both eyes showed retinal vascularization to zone II. Genetic testing revealed a heterozygous variant of uncertain significance in the catenin Alpha 1 (CTNNA1) gene. CTNNA1 gene abnormalities have been implicated as causes of familial exudative vitreoretinopathy (FEVR). It is important to recognize possible simultaneous retinopathy of prematurity and FEVR. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway.

Unveiling the Spectrum of Inborn Errors of Immunity: Lessons from T-Cell LGL Clonal Expansions

T-cell LGL clonal proliferations occur in the context of various diseases of the immune system. These associations constitute a unique research framework to discern whether the expanded clones are triggers or sequels of the concomitant disorders and, more importantly, when and how they should be targeted. While the relationship of LGL leukemia (LGLL) with autoimmune diseases is well established, the exact pathogenic connection between them remains unknown and, probably, it is not a one-way process. We previously described a syndrome whereby LGLL co-occurred with pure red cell aplasia (PRCA), thymoma, and Ig deficiency. 1 Thus, one could speculate that, paradoxically, certain forms of immunodeficiency may lead to compensatory overreactions, resulting in autoimmunity and, ultimately, in clonal LGL proliferations. Indeed, Ig deficiency is frequently encountered in our series of LGLL (n=62, 32%). While acquired conditions ( e.g., thymoma, B-cell dyscrasia) may explain some (31/62, 48%) of these cases, congenital immune defects may have a complementary, even overlapping, pathogenic contribution. Here, we identified a 36-year-old woman with history of candidiasis, IgA deficiency, T1DM and Crohn's disease, with concurrent diagnosis of PRCA and LGLL. NGS revealed a germline heterozygous variant of uncertain significance (VUS) in BACH2, a gene involved in a recently reported inborn error of immunity (IEI) characterized by lymphocyte defects, Ig deficiency, and intestinal inflammation -features all depicted in our index case. This patient inspired us to posit that germline variants involved in IEI may also contribute to the pathogenesis of LGLL. To that end, we assessed the presence of IEI defects in 90 LGLL cases by performing WGS. We screened for variants in 90 IEI genes, covering different immune pathways. After applying a stringent variant calling, rare variants were defined as those with allele freq.<1% across genome resources. Variant pathogenicity was assessed according to ACMG criteria. For analysis, we selected all pathogenic/likely pathogenic (P/LP) variants, and VUS overrepresented in our cohort (significant p-values for Obs. vs Exp. freq. after multiple-testing correction). We found 21 variants in 15 IEI genes, carried by 20 LGLL patients (22%). The combined allelic burden for these variants was 12% ( vs the expected 2% in normal population). According to the role in immunity, the variants clustered in 2 main IEI categories: autoimmunity/immune dysregulation, and combined T-/ B-cell defects ( FigA). All variants were heterozygous, and 10/21 involved genes associated with dominant traits. Four defects in 3 patients were P/LP, and mono-allelic burden of 3/4 of these variants, involving the genes PRF1, AIRE and TNFAIP3, appeared to be a sufficient basis for immune imbalance leading to disease. When we analyzed the clinical features of the carriers of IEI variants, we observed that they were associated with diagnosis of LGLL at a younger age (median: 58 vs 64 yrs., FigB), including the patient with the earliest diagnosis of LGLL in our cohort, 17 yrs., who carried a PRF1 pathogenic variant. Carriers vs non-carriers had a higher proportion of autoimmunity (63 vs 43%), Ig deficiency (33 vs 23%) and other B-cell dyscrasias (58 vs 39%). Finally, carriers also had a significantly higher prevalence of cytopenias (94 vs 73%, p=.05) and particularly immune-mediated cytopenias (42 vs 17%, p=.02) than non-carriers. Most of these associations, including the predisposition to bone marrow failure (BMF) and immune cytopenias, persisted for the carriers of P/LP and dominant defects (since VUS in genes involved in dominant vs recessive traits are more likely to be of clinical relevance). Our findings suggest that variants predisposing to IEI can be found in the setting of LGLL. For some of these cases, the genetic burden might be strong enough to overshoot autoimmunity, promoting clonal LGL expansions. Environmental agents may have cooperative roles, and particularly infections, to which these patients may be intrinsically predisposed. Such atypical cases might exhibit distinct features, e.g., earlier onset of LGLL diagnosis, or concurrent BMF, which may serve as red flags tied to the underlying adult-onset IEI. Our study proposes an alternative pathogenesis for a significant fraction of cases with LGLL, and gives us the impetus to expand the IEI spectrum to the field of BMF and clonal hematological disorders.

Riboflavin-responsive lipid-storage myopathy in elderly patients

There are scarce reports of riboflavin-responsive lipid storage myopathy in elderly patients with onset in their sixties. We describe three elderly patients with riboflavin-responsive lipid-storage myopathy. All three patients (aged 67–71 years on first examination) had subacute onset of neck extensors and proximal limb weakness progressing to inability to rise from a sitting position or to walk. Muscle biopsies showed vacuoles with lipid content, mainly in type 1 fibers. Genetic analysis failed to identify any pathogenic variant in one patient, identified a heterozygous variant of uncertain significance c.812 A > G; p.Tyr271Cys in the ETFDH gene in the second patient, and revealed a heterozygote likely pathogenic variant c.1286-2 A > C in the ETFDH gene predicted to cause abnormal splicing in the third patient. All patients responded to treatment with riboflavin and carnitine, and regained normal strength. This report emphasizes the importance of muscle biopsy in revealing treatable lipid storage myopathy in elderly patients with progressive myopathy of unidentifiable cause.

Abstract 13325: Novel Heterozygous EFEMP2 Variant Detected in a Patient With Bilateral Internal Carotid Artery Dissection and Oligodontia

Cutis laxa is a rare connective tissue disorder characterized by sagging or inelastic skin. This phenotype is caused by multiple genotype variants. Biallelic variants in the EFEMP2 gene cause cutis laxa subtype IB characterized by aortic aneurysm, arterial tortuosity, arterial stenosis, joint laxity, arachnodactyly, emphysema, and retrognathia. EFEMP2 encodes fibulin-4, an extracellular matrix protein involved in elastogenesis and modulation of TGF-beta signaling. To date, monoallelic variants in EFEMP2 have not been described as pathogenic. Furthermore, oligodontia has not been associated previously with variants in EFEMP2 . We describe a 67-year-old male with a past medical history of left distal internal carotid artery (ICA) pseudoaneurysm and dissection, right distal ICA dissection, arterial tortuosity, and oligodontia who was found to have a heterozygous variant of uncertain significance in EFEMP2: c.1279_1289del11, p.Arg427CysfsX27. The variant has not been observed previously in large population cohorts and causes a shift in reading frame that substitutes the carboxyl terminal 17 amino acids with 26 alternative amino acids. This carboxyl terminal variant of EFEMP2 has been predicted to interact with PITX2 in yeast two-hybrid analyses. Furthermore, variants in PITX2 have been associated with dental agenesis, including oligodontia. We hypothesize that heterozygous variants in EFEMP2 represent a new syndrome characterized by arteriopathy and dental agenesis.

Nemaline myopathy: reclassification of previously reported variants according to ACMG guidelines, and report of novel genetic variants.

Nemaline myopathy (NM) is a heterogeneous genetic neuromuscular disorder characterized by rod bodies in muscle fibers resulting in multiple complications due to muscle weakness. NM patients and their families could benefit from genetic analysis for early diagnosis, carrier and prenatal testing; however, clinical classification of variants is subject to change as further information becomes available. Reclassification can significantly alter the clinical management of patients and their families. We used the newly published data and ACMG/AMP guidelines to reassess NM-associated variants previously reported by clinical laboratories (ClinVar). Our analyses on rare variants that were not canonical loss-of-function (LOF) resulted in the downgrading of ~29% (28/97) of variants from pathogenic or likely-pathogenic (P/LP) to variants of uncertain significance (VUS). In addition, we analyzed the splicing effect of variants identified in NM patients by clinical laboratories or research, using an accurate in silico prediction tool that applies a deep-learning network. We identified 55 rare variants that may impact splicing (cryptic splicing). We also analyzed six new NM families and identified eight variants in NEB and ACTA1, including three novel variants: homozygous pathogenic c.164A > G (p.Tyr55Cys), and homozygous likely pathogenic c.980T > C (p.Met327Thr) in ACTA1, and heterozygous VUS c.18694-3T > G in NEB. This study demonstrates the importance of reclassifying variants to facilitate more definitive "calls" on causality or no causality in clinical genetic testing of patients with NM. Reclassification of ~150 variants is now available for improved clinical management, risk counseling and screening of NM patients.

BG11 Palmoplantar keratoderma with mutations in filaggrin and desmoglein-1 genes

Abstract Hereditary palmoplantar keratoderma (PPK) has many forms, and genetic testing can help distinguish diagnoses. This case demonstrates a presentation of PPK with an altered phenotype caused by a mutation in FLG. The patient was a 23-year-old woman referred with PPK since the age of 6 years. She reported dry skin on the back of her hands from infancy and no other dermatological conditions. She denied plantar pain except when there were fissures in the callus. There was no relevant past medical history, but a significant family history of individuals with PPK and curly hair, and sudden infant death (SID) in two siblings. Physical examination revealed focal plantar keratoderma bilaterally, curly hair, mild tongue leukokeratosis and generally dry skin on both legs. She had palmar hyperlinearity, small calluses on the palms and normal nails. She declined a skin biopsy. The patient was referred to cardiology to rule out cardiomyopathy associated with a desmoplakin variant. She had an unremarkable transthoracic echocardiography and cardiac magnetic resonance imaging. Twelve-lead electrocardiography showed sinus rhythm with biphasic T-wave in V2 and inverted V1. Clinically arrhythmogenic right ventricular cardiomyopathy (ARVC) was ruled out; however, given her significant family history of SID and PPK, panel testing for genes associated with ARVC was performed, which revealed a heterozygous variant of uncertain significance in MYBPC3 (p.Val639lle). This variant did not explain the patient’s PPK; therefore, a PPK panel was performed. Next-generation sequencing identified a heterozygous DSG1 [c430A>T p.(Arg.144*)] pathogenic variant and a heterozygous FLG [c2282_2285del p.(Ser761Cysfs*36)] pathogenic variant. The patient’s PPK was more severe on the plantar surface of the feet than one might expect with a DSG1 variant. This case demonstrates the interaction between two genetic variants known to be associated with skin conditions. Ichthyosis vulgaris is caused by FLG variants. Patients with heterozygous FLG variants are less severely affected and have reduced penetrance compared to homozygotes. Meanwhile, heterozygous pathogenic variants in DSG1 are associated with keratosis palmoplantaris striata I (MIM148700). We hypothesize that the coexistence of FLG and DSG1 variants may contribute to a more extensive keratoderma phenotype than usually seen with DSG1 variants. This case contributes to our understanding of PPK, demonstrates the value of genetic testing in dermatological conditions and describes a unique phenotype in the presence of multiple genetic variants. Further research is required to better understand the interaction between variants in PPK pathogenesis.

Use of whole genome sequencing to determine the genetic basis of visceral myopathies including Prune Belly syndrome

Objectives/aimsThe visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts, ranging from megacystis to Prune Belly syndrome. We aimed to apply a bespoke virtual genetic panel and describe novel variants associated with this condition using whole genome sequencing data within the Genomics England 100,000 Genomes Project.MethodsWe screened the Genomics England 100,000 Genomes Project rare diseases database for patients with VM-related phenotypes. These patients were screened for sequence variants and copy number variants (CNV) in ACTG2, ACTA2, MYH11, MYLK, LMOD1, CHRM3, MYL9, FLNA and KNCMA1 by analysing whole genome sequencing data. The identified variants were analysed using variant effect predictor online tool, and any possible segregation in other family members and novel missense mutations was modelled using in silico tools. The VM cohort was also used to perform a genome-wide variant burden test in order to identify confirm gene associations in this cohort.ResultsWe identified 76 patients with phenotypes consistent with a diagnosis of VM. The range of presentations included megacystis/microcolon hypoperistalsis syndrome, Prune Belly syndrome and chronic intestinal pseudo-obstruction. Of the patients in whom we identified heterozygous ACTG2 variants, 7 had likely pathogenic variants including 1 novel likely pathogenic allele. There were 4 patients in whom we identified a heterozygous MYH11 variant of uncertain significance which leads to a frameshift and a predicted protein elongation. We identified one family in whom we found a heterozygous variant of uncertain significance in KCNMA1 which in silico models predicted to be disease causing and may explain the VM phenotype seen. We did not find any CNV changes in known genes leading to VM-related disease phenotypes. In this phenotype selected cohort, ACTG2 is the largest monogenic cause of VM-related disease accounting for 9% of the cohort, supported by a variant burden test approach, which identified ACTG2 variants as the largest contributor to VM-related phenotypes.ConclusionsVM are a group of disorders that are not easily classified and may be given different diagnostic labels depending on their phenotype. Molecular genetic analysis of these patients is valuable as it allows precise diagnosis and aids understanding of the underlying disease manifestations. We identified ACTG2 as the most frequent genetic cause of VM. We recommend a nomenclature change to ‘autosomal dominant ACTG2 visceral myopathy’ for patients with pathogenic variants in ACTG2 and associated VM phenotypes.

A Case of a Relapsing Remitting Macrophage Activating Syndrome After Covid-19 Vaccine In a Teenager with UNC13D Heterozygous Variant of Uncertain Significance

IntroductionMacrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case PresentationA 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron; however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. DiscussionMAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Display omitted] [Display omitted] [Display omitted]

POLG-Related Ataxia and Ophthalmoplegia: A Case Report (P9-11.008)

<h3>Objective:</h3> Not applicable <h3>Background:</h3> Genetic variants of the POLG gene result in mitochondrial DNA defects and account for a large proportion of mitochondrial diseases. These disorders encompass a spectrum of phenotypes, with onset ranging from infancy to late adulthood. In addition to hepatic dysfunction and myopathy in younger populations, and hormone derangements with cataracts in older patients, patients may also present with prominent neurologic symptoms, including ataxia, parkinsonism, epilepsy, and ophthalmoplegia. More than 300 pathogenic mutations of POLG have been reported and there are no clear genotype-phenotype correlations. Given the rarity of these syndromes and wide range of clinical phenotypes, there is often delay in diagnosis. <h3>Design/Methods:</h3> Not applicable <h3>Results:</h3> We present a 47-year old woman with symptoms of difficulty speaking and development of tremor, vision loss, dizziness, and gait difficulty progressing over several months. Initial exam was significant for ataxia and choreiform movements. Extraocular movement (EOM) testing revealed delayed initiation of saccades and slow, saccadic pursuits with nystagmus. Bloodwork, which included extensive workup for causes of chorea and ataxia, electromyography/nerve conduction studies, and imaging (MRI brain and malignancy work-up) were unremarkable. She continued to decline with development of ophthalmoplegia, ptosis, numbness, weakness, and pain, severely limiting her functional capacity. Whole exome sequencing was performed and showed a heterozygous variant of uncertain significance (VUS) in the POLG gene, which may explain her presentation. <h3>Conclusions:</h3> This case adds to a growing collection of case reports describing the various phenotypes of POLG-related disorders. Early detection of POLG variants and phenotype/genotype characterization may help guide development of future treatments for patients with similar conditions. <b>Disclosure:</b> Dr. Peabody has nothing to disclose. An immediate family member of Dr. Shpiner has received personal compensation for serving as an employee of University of Miami.

Detection of a de novo heterozygous ANK2 variant in a child with autism spectrum disorder and epilepsy: a case report

BackgroundThe pathogenesis of autism spectrum disorder (ASD) is not fully clarified. Next-generation sequencing technologies have greatly enhanced the identification of new genes associated with ASD. Variants in ANK2 gene are known to correlate with a broad spectrum of clinical cardiac phenotypes, but, more recently, it has also been pointed out as a candidate gene for the etiology of ASD.Case presentationWe report the case of a female patient with ASD and epilepsy in whom clinical exome sequencing was performed for etiological enlightenment. A heterozygous variant of uncertain significance was identified in the ANK2 gene: c.3412C > T p.(Arg1138Ter). The child was submitted to a formal cardiac evaluation, ruling out cardiovascular abnormalities. The genetic variant was searched in her parents and was negative in both, suggesting a de novo variant, which favors its pathogenicity.ConclusionsWe recognize the challenge of assessing variant pathogenicity in candidate genes for ASD, and ANK2 gene is currently not associated with neurodevelopmental disorders in the Online Mendelian Inheritance in Man database. Nonetheless, our case can be added to other published reports of de novo ANK2 variants in children with ASD and neurological phenotypes (including seizures), some without cardiac impairment. Hopefully, this study provides a more detailed phenotypical description that is often lacking, and it may contribute to a better understanding of the association between ANK2 and ASD.

Heterogeneous phenotype of autoinflammatory disease in a patient with mutations in NOD2 and MEFV genes

Background: Autoinflammatory diseases are a genetically heterogeneous group of conditions characterized by excessive activation of the innate immune system. They frequently present with overlapping features, particularly in cases of digenic or polygenic inheritance. The most common cause of autoinflammation arises from causative variants in the MEFV gene, responsible for familial Mediterranean fever. Clinical features include recurrent episodes of fever with serositis and amyloidosis. Individuals with variants in MEFV that present atypically with heterogeneous autoinflammatory features have also been described. Notably, gene modifiers of MEFV, such as NOD2 encoding an intracellular bacterial sensor, can result in more severe disease. NOD2 underlies a number of autoinflammatory and immunodeficiency conditions, including Blau syndrome. To date, Blau syndrome has not been described in the context of MEFV. Aim: To expand the presentation and phenotype of autoinflammatory disease associated with defects in the NOD2 and MEFV genes. Methods: A retrospective review of the patient’s chart was performed, including family history, medical history, immune laboratory evaluation, and genetics. Results: We describe here a 68-year-old male with a remarkable medical history since childhood of skin rash, erythroderma, recurrent infections, autoinflammation, arthritis, uveitis, and malignancy. A significant family history of cancer and autoinflammation was noted. Genetic work-up involving a 17-gene autoinflammatory panel revealed 3 heterozygous variants of uncertain significance, 2 of which were present in the MEFV gene and one in the NOD2 gene. His features were consistent with an overlapping phenotype of Blau syndrome and atypical FMF. Conclusion: Heterozygous variants in NOD2 and MEFV can result in a spectrum of autoinflammatory disorders with a heterogeneous phenotype. The NOD2 variant identified in our patient has not previously been associated with Blau syndrome. Statement of Novelty: We describe a patient harbouring heterozygous mutations in the MEFV and NOD2 genes marked by recurrent childhood infections.

ODP149 Hypertriglyceridemia-Induced Acute Pancreatitis in Second Trimester of Pregnancy

Abstract Background Acute pancreatitis (AP) during pregnancy is a rare, potentially life-threatening disease, with an incidence of 1 case per 1,000-10,000. Hypertriglyceridemia (HTG)-induced pancreatitis accounts for only 5% of cases. Here we describe a rare case of HTG-induced AP during the second trimester of pregnancy, which was treated with concurrent insulin and plasmapheresis. Clinical Case A 35-year-old multigravida female was admitted for preterm premature rupture of membranes at 26 weeks gestation. Symptoms began on day 8 of admission and included severe epigastric pain radiating to the back. On exam, there was significant epigastric tenderness on palpation. There were no xanthelasmas or tendon xanthomas seen. She was afebrile but tachycardic. Laboratory evaluation noted a triglyceride (TG) level of &amp;gt;5,680 mg/dL (n&amp;lt;150), amylase 201 U/L (n&amp;lt;100) and lipase 277 U/L (n&amp;lt;60), consistent with AP. She was euglycemic. CT of the abdomen showed interstitial edematous pancreatitis with a peripancreatic collection. She was placed on NPO and started on intravenous (IV) fluid therapy, in combination with IV insulin and 10% dextrose. The patient also underwent one session of plasmapheresis. TG levels downtrended rapidly to 3,585 mg/dL within 24 hours. Once TG levels decreased below 1,000 mg/dL, insulin and dextrose infusions were stopped, and combination therapy of fenofibrate, omega-3 fatty acids, and low-fat low-carbohydrate diet was started. At 28 weeks and 5 days gestation, a cesarean section was performed due to suspected fetal distress. The patient was discharged on fenofibrate and Omega-3 fatty acids with a TG level of 456 mg/dL. Genetic testing revealed a heterozygous variant in the LPL gene mutation (c.644G&amp;gt;A; p. Gly215Glu) and a heterozygous variant of uncertain significance (VUS) in the ABCA1 gene (c.1765G&amp;gt;A; p. Val589Ile). She had no known family history of hyperlipidemia or cardiovascular disease. Conclusion Lipoprotein lipase (LPL) deficiency is an autosomal recessive disorder caused by biallelic pathogenic mutations in the LPL gene. The heterozygous c.644G&amp;gt;A variant has been previously described in several patients with LPL deficiency, however its impact on the function of the LPL protein has not yet been clearly defined. The ABCA1 gene is associated with Tangier disease, characterized by very low HDL levels and HTG. The ABCA1 gene variant detected in this case is classified as VUS as its effect on the gene function is not yet known. Further investigation is warranted to understand the role of these variants in familial dyslipidemia. Aside from the described patient, only one other case report of HCT-induced AP treated with concomitant plasmapheresis and IV insulin therapy has been reported in the literature. There are no published guidelines regarding the optimal treatment for HTG-induced AP in pregnancy. Combined treatment modality with plasmapheresis and IV insulin seems to be effective, however, its risks and benefits should be carefully assessed. Presentation: No date and time listed

RECURRENT LUNG INFECTIONS IN A HETEROZYGOUS CARRIER OF NOVEL NSMCE3 MUTATION.

<h3>Introduction</h3> Several biallelic missense mutations in NSMCE3 lead to chromosome breakage syndrome (LICS), which presents with early-onset lung disease, pneumonia, B- and T- cell dysfunction and resultant death in early childhood. The protein product of NSMCE3 helps bridge and stabilize the SMC5/6 complex, which plays a crucial role in DNA double-strand break repair and is thought to help suppress viral infections. <h3>Case Description</h3> A 5-year-old male with atopic dermatitis and reactive airway disease presented for evaluation of recurrent sinopulmonary infections. In one year, he had three episodes of acute otitis media and five viral upper respiratory infections, complicated by multiple bacterial pneumonias. Initial immunologic workup showed low CD8+ T-cells that subsequently normalized. He also had marginally-low IgM, but showed intact humoral response to HiB vaccine and Pneumovax. Three years later, he experienced two more episodes of bacterial pneumonia, one requiring two rounds of antibiotics for clinical improvement. Genetic testing (Invitae Primary Immunodeficiency Panel) showed a heterozygous variant of uncertain significance, a deletion-insertion mutation of the NSMCE3 gene (nucleotides 41 and 42 are deleted and two cytosines inserted, which changes glutamine to proline at the 14th amino acid position in the protein product). <h3>Discussion</h3> In most cases, heterozygous carriers can compensate for a defective allele. Our patient has a missense mutation in one NSMCE3 allele, which may affect the protein product's conformation. Since this protein functions in DNA repair and known mutations have been associated with pneumonia and viral infections, we hypothesize that his reduced level of normal protein may underlie his recurrent pneumonias.

AN ATYPICAL PRESENTATION OF LIPOPOLYSACCHARIDE-RESPONSIVE BEIGE-LIKE ANCHOR PROTEIN DEFICIENCY

<h3>Introduction</h3> Lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency is associated with diarrhea, autoimmune disorders, organomegaly, recurrent infections, hypogammaglobulinemia, chronic lung manifestations, and growth retardation. However, LRBA mutations show a wide range of phenotypic variability. We present a case of a sixteen-year-old girl with a variant of uncertain significance (VUS) in the LRBA gene with atypical symptoms of LRBA deficiency. <h3>Case Description</h3> The patient is a sixteen-year-old female with type one diabetes mellitus, chronic urticaria, and idiopathic anaphylaxis requiring admission. Her complete blood count with differential, B and T cell phenotyping, and immunoglobulin levels were normal. She failed high dose antihistamines and omalizumab. Due to atypical symptoms, including soft tissue swelling, joint pains, recurrent abdominal pain, and elevated interleukin 10, interleukin 6, and S100 during an episode, we obtained an auto-inflammatory panel that showed a heterozygous VUS mutation in the LRBA gene. Parental LRBA testing showed the variants were trans-acting, increasing the likelihood that the variants contribute to her phenotype. She was started on abatacept with hydroxychloroquine, which improved her symptoms. <h3>Discussion</h3> This case highlights an atypical presentation of LRBA deficiency presenting with chronic urticaria and idiopathic anaphylaxis with a normal immune work up, symptoms of which are responsive to abatacept and hydroxychloroquine.

S3198 Was It Always in the Genes? ABCB4 and Its Variable Presentations

Introduction: Progressive familial intrahepatic cholestasis (PFIC), low phospholipid-associated cholestasis (LPAC), and autosomal dominant intrahepatic cholestasis of pregnancy (ICP) are rare genetic disorders that should be considered in patients with elevated alkaline phosphatase and unrevealing primary work ups. We present a case of a 36-year-old female with a history of ICP who presented with elevated ALP, eventually found to have a nonspecific variant in the ABCB4 gene, concerning for Type 3 PFIC. Case Description/Methods: A 36-year-old female with a history of ICP treated with Ursodiol, current oral contraceptive use (OCP), and remote cholecystectomy presented to a gastroenterologist for asymptomatic ALP elevation. Initial labs revealed ALP 279 U/L, bile acids 9.9 μmol/L, and gamma-glutamyl transferase (GGT) 283U/L. Magnetic resonance cholangiopancreatography (MRCP) was unrevealing. Given no signs of hepatic dysfunction, portal hypertension, or steatosis on fibroscan, liver biopsy was obtained, which was unremarkable. Due to persistent elevation in ALP without a clear etiology and history of ICP, genetic testing was pursued. Genetic testing revealed a heterozygous variant of uncertain significance in the ABCB4 gene that is associated with PFIC type 3. OCPs were discontinued due to an association of ICP and OCP induced cholestasis. Ursodiol was restarted given high rates of recurrent cholelithiasis in patients with PFIC. Discussion: Type 3 PFIC, LPAC, and ICP are rare genetic disorders linked to unique mutations in the ABCB4 gene responsible for ALP elevation. The ABCB4 gene may manifest later in life as cholestasis, jaundice, or pruritus. Mutations in the ABCB4 gene can cause a reduction in biliary phospholipid concentration, leading to sludge, cholesterol stones, and microlithiasis. Type 3 PFIC has a unique presentation associated with elevated GGT, unseen in type 1 or 2. LPAC should be considered in patients presenting with cholelithiasis before the age of 40, recurrent cholithialsis after cholecystectomy, ICP, and family history of cholelithiasis. The variant of uncertain significance in our patient’s ABCB4 gene appeared to be a unifying diagnostic factor given her history of ICP, cholelithaisis at age 18 years requiring cholecystectomy, and persistent new elevation in ALP. She ultimately met criteria for Type 3 PFIC, LPAC and ICP. Given the rapidly evolving nature of medical genetics, reclassification and evaluation of genetic mutations requires follow up.

Hemimegalencephaly and Epileptic Encephalopathy Associated with a Variant of Uncertain Significance of the TRIO Gene

Objectives: Electrical status epilepticus during sleep (ESES) is a type of EEG pattern seen in children with childhood-onset epileptic seizures and cognitive, language and motor regression. ESES has been associated with different etiologies, with or without structural abnormalities of the brain. To replace the term “ESES”, the recent Position Paper of the ILAE Taskforce on Nosology and Definitions introduced the term Epileptic Encephalopathy with Spike-Wave Activity during Sleep (EE-SWAS), which represents an activation of epileptiform activity, typically 1.5-2.5 Hz during NREM sleep, in a previously normal child and leads to cognitive and motor regression. Pathogenic variants in the TRIO gene are associated with autosomal dominant mental retardation type 44 (MRD44), which is characterized by mildly delayed global development resulting in variable intellectual deficits, learning difficulties, and variable dysmorphic features mostly represented by facial asymmetry, microcephaly, abnormalities of the fingers, and dental anomalies. Materials and methods: We present the case of a 13-year-old girl with onset of atonic seizures at the age of 3 who had undergone different types of antiepileptic drug (AED) therapies and was seizure-free 4 years later. She had an acquired impaired cognitive status as well as hemimegalencephaly, multiple hypopigmented patches on her legs and a large patch of hypopigmentation on the left side of her face extending towards the scalp (Becker’s nevus), dental anomalies (gingival hyperplasia, ogival palate), periventricular gliosis and electroencephalographic and (EEG) findings consistent with SWAS. Outcomes: Genetic testing confirmed a heterozygous variant of uncertain significance (VUS) of the TRIO gene, possibly associated with autosomal dominant MRD44. Although our patient presented with some phenotypic similarities to MRD44, her cognitive impairment improved with control of the SWAS pattern and AED adjustments. Conclusion: Association of structural anomalies of white matter, hemimegalencephaly, and encephalopathy with SWAS and a VUS mutation of the TRIO gene might suggest a different genetic neurocutaneous syndrome altogether.

Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents

PurposeExamining a cohort of patients suspicious of neurofibromatosis type 1 (NF1) we compared the revised diagnostic criteria with the previous National Institutes of Health (NIH) diagnostic criteria. We asked whether the refinement improved distinguishing between NF1, Legius syndrome, and constitutional mismatch repair deficiency (CMMRD). MethodsA database search in the hospital information system of the University Children’s Hospital Augsburg between 2017 and 2020 ascertained patients with International Classification of Diseases-10 code Q85.0; their clinical phenotype was evaluated by retrospective chart review. ResultsA total of 75 patients were identified (median age 11.0 years [range 1.1-22.6 years]; 35 female). At first suspicion of NF1, 44 patients met the NIH criteria and 56 met the revised diagnostic criteria. In total, 12 patients were diagnosed with NF1 after performing molecular genetic testing. In 31 patients, only pigmentary findings were present, whereas nonpigmentary NF1 manifestations presented with time in 9 patients. In 1 patient a heterozygous variant of uncertain significance was identified in SPRED1. Requirements for CMMRD testing were fulfilled in another patient. A total of 3 patients presented with segmental clinical findings. Three additional patients did not meet the NIH criteria, 1 of them presented with 1 additional feature of CMMRD without fulfilling requirements for testing. ConclusionIn our pediatric cohort, the revised diagnostic criteria discovered more patients with proven NF1 than the NIH criteria.

P.042 A novel SOD1 mutation associated with rapidly evolving lower motor neuron syndrome and MR ventral nerve root enhancement

Background: Mutations in the Cu/Zn superoxide dismutase 1 (SOD 1) gene are estimated to cause 20% of familial ALS and 1-2% of sporadic cases. Accurate gene variant classification of novel mutations in amyotrophic lateral sclerosis (ALS) has deepened our understanding of clinical phenotypes, provided pathologic insights, and is crucial to incorporating emerging therapies. Methods: We describe a case of a 75-year-old female who presented with a rapidly progressive lower motor neuron syndrome leading to flaccid quadriparesis and complete loss of independence over a five month period. Results: Genetic testing demonstrated a heterozygous variant of uncertain significance in the SOD1 gene with a g &gt; c point mutation at position 382 that has been described in one other patient in available literature. MR of the lumbar spine demonstrated abnormal smooth nerve root enhancement. Conclusions: This novel mutation in the SOD1 gene may be associated with a rapidly progressive phenotype of sporadic ALS. Ventral nerve root enhancement should not exclude a diagnosis of ALS especially in the absence of nodularity or nerve enlargement.