Search Results (697)

Background and Clinical Significance: Wilson disease is a rare autosomal recessive disorder of copper metabolism that can initially present with psychiatric symptoms, leading to delays in accurate diagnosis and treatment. Adult-onset cases may be misdiagnosed as primary psychiatric disorders, particularly when hepatic signs are subtle or absent. Early recognition is critical to prevent irreversible neurological and hepatic damage. Case Presentation: A 48-year-old Hispanic male developed persecutory delusions, cognitive decline, and ultimately catatonia over a three-year period. He was initially diagnosed with a primary psychiatric disorder and treated with antipsychotics, which caused severe extrapyramidal side effects. Further evaluation revealed markedly abnormal liver function tests, low serum ceruloplasmin, and elevated 24 h urinary copper excretion. Brain MRI showed characteristic findings of Wilson disease, and liver biopsy confirmed the diagnosis. The patient was started on trientine and zinc sulfate, but progressive hepatic dysfunction necessitated liver transplantation. Following a successful transplant, the patient experienced significant neurological and psychiatric recovery. Conclusions: This case underscores the importance of considering Wilson disease in patients presenting with atypical or treatment-resistant psychiatric symptoms, particularly when accompanied by abnormal liver function or intolerance to antipsychotics. Timely, multidisciplinary evaluation is essential to avoid misdiagnosis and initiate appropriate therapy. Early intervention can significantly improve both psychiatric and medical outcomes in Wilson disease. Full article

Background: Pathogenic variants in interphotoreceptor matrix proteoglycan 1 (IMPG1) have been associated with autosomal dominant and recessive retinitis pigmentosa (RP) and autosomal dominant adult vitelliform macular dystrophy (AVMD). Monoallelic pathogenic variants in IMPG2 have been linked to maculopathy and biallelic variants to RP with early onset macular atrophy. Herein we characterise the phenotypic and genotypic features of patients with IMPG1/IMPG2 retinopathy and report novel variants. Methods: Patients with IMPG1 and IMPG2 variants and compatible phenotypes were retrospectively identified. Clinical data were obtained from reviewing the medical records. Phenotypic data included visual acuity, imaging included ultra-widefield pseudo-colour, fundus autofluorescence, and optical coherence tomography (OCT). Genetic testing was performed using next generation sequencing (NGS). Variant pathogenicity was investigated using in silico analysis (SIFT, PolyPhen-2, mutation taster, SpliceAI). The evolutionary conservation of novel missense variants was also investigated. Results: A total of 13 unrelated patients were identified: 2 (1 male; 1 female) with IMPG1 retinopathy and 11 (7 male; 4 female) with IMPG2 retinopathy. Both IMPG1 retinopathy patients were monoallelic: one patient had adult vitelliform macular dystrophy (AVMD) with drusenoid changes while the other had pattern dystrophy (PD), and they presented to clinic at age 81 and 72 years, respectively. There were 5 monoallelic IMPG2 retinopathy patients with a maculopathy phenotype, of whom 1 had PD and 4 had AVMD. The mean age of symptom onset of this group was 54.2 ± 11.8 years, mean age at presentation was 54.8 ± 11.5 years, and mean BCVAs were 0.15 ± 0.12 logMAR OD and −0.01 ± 0.12 logMAR OS. Six biallelic IMPG2 patients had RP with maculopathy, where the mean age of onset symptom onset was 18.4 years, mean age at examination was 68.7 years, and mean BCVAs were 1.90 logMAR OD and 1.82 logMAR OS. Variants in IMPG1 included one missense and one exon deletion. A total of 11 different IMPG2 variants were identified (4 missense, 7 truncating). A splicing defect was predicted for the c.871C>A p.(Arg291Ser) missense IMPG2 variant. One IMPG1 and five IMPG2 variants were novel. Conclusions: This study describes the phenotypic spectrum of IMPG1/IMPG2 retinopathy and six novel variants are reported. The phenotypes of PD and AVMD in monoallelic IMPG2 patients may result from haploinsufficiency, supported by the presence of truncating variants in both monoallelic and biallelic cases. The identification of novel variants expands the known genetic landscape of IMPG1 and IMPG2 retinopathies. These findings contribute to diagnostic accuracy, informed patient counselling regarding inheritance pattern, and may help guide recruitment for future therapeutic interventions. Full article

Background/Objectives: Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections. Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted. We present a pediatric case from Kazakhstan to broaden the clinical and molecular spectrum of TYK2-related immunodeficiency and accentuate diagnostic challenges. Methods: The proband underwent clinical assessment, immunophenotyping, and biochemical analysis during episodes of active pathology and subsequent follow-up. Whole-exome sequencing (WES) was executed, followed by confirmatory Sanger sequencing and segregation analysis in first-degree kin. Functional assays for phagocyte oxidative burst and phagocytosis were conducted to exclude CGD. Results: WES identified two rare TYK2 variants (c.209_212del, pathogenic; c.2395G>A, previously reported as pathogenic in a Chinese patient with TYK2 deficiency) and a heterozygous MEFV duplication (c.761_764dup). Paternal DNA was unavailable; therefore, allelic phase could not be formally established, but the combined genotype and phenotype are consistent with autosomal recessive TYK2 deficiency. Sanger sequencing confirmed segregation of the frameshift TYK2 variant in the mother, while the clinically healthy brother carried only the wild-type allele. The missense alteration was exclusive to the proband. Conclusions: This case exemplifies the significance of contemplating TYK2 deficiency in pediatric patients with refractory mycobacterial infections, particularly in BCG-endemic locales. Genetic validation provided a definitive diagnosis, differentiating the condition from CGD and informing patient management. To our knowledge, this constitutes one of the inaugural genetically confirmed instances of TYK2 deficiency in Central Asia, enhancing regional epidemiological comprehension and emphasizing the role of molecular diagnostics in directing treatment and vaccination policies. Full article

Marinesco–Sjögren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, developmental delay, hypotonia, and progressive myopathy. Most reported cases are linked to pathogenic variants in SIL1, a gene encoding a co-chaperone essential for protein folding in the endoplasmic reticulum. Here, we present a comprehensive case study of a Turkish pediatric patient diagnosed with MSS, supported by genetic, bioinformatic, and structural modeling analyses. Whole-exome sequencing revealed a homozygous splice-site variant (SIL1 c.453+1G>T), confirmed by Sanger sequencing and segregation analysis. In silico annotation using Genomize, InterVar, Franklin, VarSome, ClinVar, OMIM, and PubMed classified the variant as pathogenic according to ACMG guidelines. Structural modeling by Phyre2 and I-TASSER demonstrated that the variant abolishes the intron 5 donor site, leading to truncation of the wild-type 461-amino-acid protein into a shortened ~189-amino-acid polypeptide. This truncation results in the loss of critical Armadillo (ARM) repeats required for HSPA5 interaction, explaining the observed instability and impaired chaperone function. Clinically, the patient presented with congenital cataracts, ataxia, developmental delay, and progressive muscle weakness, consistent with previously reported MSS cases. Comparison with the literature confirmed that splice-site variants frequently correlate with severe phenotypes, including early-onset ataxia and cataracts. This report highlights the importance of integrating genomic, structural, and clinical data to better understand genotype–phenotype correlations in MSS. Our findings expand the mutational spectrum of SIL1, reinforce the role of splicing defects in disease pathogenesis, and emphasize the necessity of comprehensive molecular diagnostics for rare neurogenetic syndromes. Full article

Objective: The genetic causes of obesity are complex and include diabetes and obesity monogenic syndromes like autosomal recessive Bardet–Biedl syndrome (BBS). Other clinical manifestations of this syndrome include metabolic disorders, polydactyly, retinal dystrophy, and endocrine, urological, and neurological abnormalities. Moreover, isolated clinical manifestations have been described in carriers of heterozygous mutations in BBS genes. On the other hand, Fahr’s disease is characterized by the accumulation of calcium deposits in various areas within the brain, leading to neurodegeneration, and the course of the disease is variable. Case presentation: We present the case of a 21-year-old female with severe obesity, diagnosed at the age of six years. The patient also experienced hypertension, hyperlipidemia, insulin resistance, and polycystic ovarian syndrome. During an MRI examination, hyperintensity in the region of the dentate nuclei and hyperintensity in the globus pallidus were described. NGS (next-generation sequencing) results showed a heterozygous variant in the TMEM67 gene, which revealed the patient to be a carrier of BBS, and a homozygotic variant in the MYORG gene, leading to a Fahr’s disease diagnosis. However, due to an insufficient number of phenotypic criteria and only one causative variant in the TMEM67 gene, the diagnosis of BBS could not be established. Conclusions: Attempts to identify the cause of obesity can lead to unexpected results, which can be resolved through collaboration between clinicians of different specialties and the use of NGS molecular testing. The status of being a BBS carrier, which coexists with Fahr’s disease, may be a potential contributing factor to severe obesity and metabolic disorders in the patient. Full article

Inherited platelet function disorders (IPFDs) are rare diseases caused by defects in platelet surface receptors, enzymes, granules, or signaling proteins. In humans, GPVI and P2Y12 deficiency cause autosomal recessive bleeding disorders, while TBXAS1 deficiency is related to Ghosal hematodiaphyseal dysplasa, a rare autosomal recessive disorder characterized by increased long bone density and platelet dysfunction without bleeding. To date, at least 20 patients have been identified with molecular defects in P2RY12, 12 cases with molecular defects in GP6, and 34 cases with molecular defects in TBXAS1. Here, we report a novel nonsense and missense variants in P2RY12, a novel nonsense variant in GP6, and a novel missense variant in TBXAS1. These variants selectively affect the platelet reactivity to ADP and collagen/CRP, predisposing to bleeding. P2RY12 c.835 G>A [p.Val279Met] variant did not affect receptor expression whereas P2RY12 c.44delG [p.Ser15Ilefs*33] lead to decreased levels of the receptor in one of the patients. This was confirmed both by RT-qPCR and immunoblotting analysis. Decreased expression of both GPVI and FcRγ-chain was detected in patients carrying GPVI nonsense variant in heterozygosis. The deleterious effect of these variants was also confirmed in a transfected cell line model. TBXAS1 variant triggered decreased TxA₂ production using a cell line model. These variants expand the genetic landscape of P2RY12, GPVI and TBXAS1 inherited deficiency. Full article

Autosomal recessive (AR) disorders represent a significant public health challenge, as asymptomatic carriers are often unaware of their reproductive risks. This study provides the first comprehensive assessment of AR gene variant frequencies and their molecular landscape in a fertile Western Romanian population. Genetic results from 604 unrelated, unaffected Caucasian individuals of reproductive age, tested at a single genetic center between 2020 and 2024, were retrospectively analyzed. Next-generation sequencing (NGS) with a multi-gene panel targeting 300 AR-associated genes was used for molecular profiling. Variants were identified in 156 genes, with 75% of individuals carrying at least one AR variant (mean 1.77 variants/person). A subgroup with >3 pathogenic variants comprised 7.5%, posing a notable risk for future offspring. The most frequent variants were detected in HFE (1:5), CFTR (1:9), BTD (1:16), GJB2 (1:17), and CYP21A2 (1:19). Four variants (HFE, c.187C>G; BTD, c.1330G>C; CFTR, c.1210-34TG[11]T[5]; GALT, c.-119_-116del) were particularly prevalent, each exceeding 3% frequency. Considerable allelic heterogeneity was observed for distrinctive variants in CFTR (14), PAH (12), USH2A (12), and ATP7B (9). Several variants were linked to severe disorders, with CFTR, GALT, ATP7B, and SMN1 identified as “red zone” genes associated with high morbidity and mortality. Low-frequency variants formed a “long tail” (83.9%), reflecting marked population heterogeneity and potential hidden disease risks. The study reveals high allelic diversity and a strong prevalence of AR variants in Western Romania. Variant-based gene classification supports population-level screening, highlighting the public health value of a national program to identify carriers and prevent severe inherited disorders. Full article

Background: Inherited retinal dystrophies (IRDs) include a clinically and genetically diverse array of conditions resulting in progressive visual impairment. The PROM1 gene is crucial for the development and maintenance of photoreceptors. Variants in PROM1 are linked to a wide phenotypic spectra of IRDs; however, the correlation between genotype and phenotype is not fully elucidated. Comprehending these relationships is essential for enhanced diagnostic precision, patient guidance, and formulation of focused treatments. Objective: This study aims to examine the genotype–phenotype associations in patients with PROM1-associated IRDs. Clinical variability and inheritance patterns linked to different pathogenic variants are examined, aiming to clarify their different behaviors. Methods: We performed a retrospective investigation of patients identified as affected by PROM1-related IRDs. Thorough ophthalmologic assessments, including retinography, fundus autofluorescence, optical coherence tomography (OCT), and electrodiagnostic testing (EDT), were conducted. Genetic testing was performed via targeted gene panels or whole-exome sequencing. Variants were categorized based on ACMG criteria, and inheritance patterns were determined by familial segregation analysis. Clinical characteristics were analyzed among genotypic groups to ascertain potential phenotype–genotype relationships. Results: All patients had pathogenic or likely pathogenic PROM1 mutations. Both autosomal dominant and autosomal recessive inheritance patterns were identified. Dominant pathogenic variants were predominantly linked to late-onset cone-rod dystrophy or macular dystrophy, whereas biallelic variants frequently resulted in early-onset severe rod–cone dystrophy characterized by fast vision deterioration. A group of patients with the same genotypes displayed significant phenotypic variability, indicating the potential impact of modifier genes or environmental influences. Truncating mutations in the N-terminal region were significantly associated with earlier illness onset and greater functional impairment. Conclusions: PROM1-related IRDs demonstrated significant clinical and genetic heterogeneity, with the route of inheritance and type of variant affecting disease severity and progression. Our findings underscore the significance of thorough genotypic and phenotypic characterization in afflicted individuals. A deeper comprehension of PROM1-related IRD disease pathways can enhance prognosis, direct clinical care, and facilitate the advancement of genotype-based therapy strategies. Full article

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease with an autosomal recessive trait caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme, which leads to the accumulation of chondroitin-6-sulfate and keratan sulfate, primarily in cartilage and its extracellular matrix, resulting in a direct impact on cartilage and bone development, as well as subsequent systemic skeletal dysplasia. ERT and HSCT are current treatment options, but they have a limited effect on bone lesions. In this article, we investigated liver-specific AAV8 vectors with a thyroxine-binding globulin promoter in the MPS IVA murine model to evaluate the long-term (24 weeks in males and 48 weeks in females) effects of gene therapy on biochemical markers and bone pathology. Both treated groups showed GALNS enzyme activity at supraphysiological levels in plasma and in various tissues, including the liver, heart, spleen, and bone. Keratan sulfate in both groups was normalized in plasma, liver, and bone (male mice). Pathological analyses revealed a decrease in vacuolated cells in the heart muscle and valves and improvement in bone pathology in treated male mice. However, the therapeutic impact was less pronounced in treated female mice. Overall, male mice indicated a substantial improvement in biochemical parameters and pathology compared to female mice. Full article

Gaucher disease (GD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The pathogenic defects result in a misfolded protein, which can trigger endoplasmic reticulum stress and an unfolded protein response within the affected cells. The reduced enzyme activity leads to accumulation of its substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), within lysosomes or macrophages and with prominent disease manifestations in reticuloendothelial tissues such as liver, spleen and bone marrow. GCase defects alter both the mitochondria and the lysosome. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby activating α-synuclein accumulation. GCase can also be imported into the mitochondria, where it fosters the integrity and function of mitochondrial respiratory chain (MRC) complex I. Thus, the reduced GCase activity impairs the normal mitochondrial function and increases oxidative stress in this organelle, which may contribute to cell death. However, further studies are required to confirm this mechanism of MRC dysfunction. In this review we have systematically evaluated the evidence for oxidative stress in individuals affected by GD, as well as the currently available therapies and adjunctive therapies. Therapies targeting oxidative stress may prove useful as adjuvant treatments for GD. Full article

Background/Objectives: Inborn errors of immunity (IEIs), formerly known as primary immunodeficiency disorders, are a heterogeneous group of genetic diseases characterized by recurrent infections and multisystem involvement. Although more than 500 distinct entities have been identified, reports from Central Asia remain scarce. This study describes two rare pediatric IEI cases from Kazakhstan, highlighting the importance of genomic diagnostics in underrepresented regions. Methods: Two unrelated male patients with early-onset recurrent infections and systemic complications were evaluated at the University Medical Center, Astana. Clinical and laboratory assessments included immunophenotyping, imaging, and histopathology. Whole-genome sequencing (WGS) was performed, followed by Sanger confirmation and segregation analysis when feasible. Variants were classified according to ACMG/AMP guidelines. Results: The first case involved a child with recurrent bronchopulmonary disease, pulmonary fibrosis, and connective tissue abnormalities, found to carry a novel homozygous FBLN5:c.53del frameshift variant consistent with autosomal recessive cutis laxa type 1A. The second case concerned an adolescent with progressive neurodegeneration, granulomatous skin lesions, and chronic pancreatitis, who was identified with a heterozygous pathogenic ATM:c.4828dup variant, confirming ataxia–telangiectasia. Both patients required lifelong subcutaneous immunoglobulin therapy. Consanguinity contributed to the genetic risk in the first case, while the second case demonstrated diagnostic delays that emphasized the value of genetic testing. Conclusions: These cases underscore the clinical heterogeneity of IEIs and illustrate the essential role of genomic diagnostics in elucidating atypical presentations. Documenting rare variants and unconventional phenotypes enhances global knowledge, elevates awareness in resource-limited regions, and emphasizes the necessity for early, multidisciplinary care and the enhancement of national registries for rare immunogenetic disorders. Full article

Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare form of PKD that leads to the development of multiple renal cysts and hepatic fibrosis. Aim: The first documented case of large hepatic cyst associated with dual PKHD1-PKD1 variants. Case report: We present the case of a 5-year-old boy with a kidney US image typical of ARPKD and numerous large cysts in the liver not typical for this disease. Genetic analysis revealed heterozygous missense mutations in the PKHD1 gene (maternally, c.107C>T/p.Thr36Met in exon 3; paternally, c.4870C>T/p.Arg1624Rrp in exon 32) and an additional new variant in PKD1 (maternally, c.5323G>A/p.Gly1775Ser in exon 32). Genetic tests excluded mutations in genes responsible for polycystic liver disease (PCLD). However, the presence of the PKD1 mutation is clinically not clear due to the normal abdominal US image in the mother; it seems to be the most likely explanation for unusual phenotype in our patient. Conclusions: This case may contribute to the understanding of the phenotypic variability in ARPKD and the potential modifying role of mutations in other PKD-related genes. Comprehensive genetic panels are crucial for explaining atypical phenotypes and prognosis in patients with PKD. Full article

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene, which encodes a cAMP-activated chloride channel essential for epithelial function. Beyond its canonical role, evidence suggests CFTR also influences mitochondrial function. Previous studies have identified CFTR- and Cl-dependent genes, including MTND4 and CISD1, which are downregulated in CF cells and play a critical role in mitochondrial function. CF cells exhibit altered mitochondrial complex I (mCx-I) activity and impaired electron transport chain function, although the underlying mechanisms remain unclear. In this study, the impact of the CFTR modulators lumacaftor (VX-809) and ivacaftor (VX-770) on mitochondrial morphology and function was investigated in heterozygous ΔF508/W1282X CF IB3-1 cells. Combined treatment with VX-809 (10 μM, CFTR corrector) and VX-770 (0.1 μM, CFTR potentiator) induced a fragmented mitochondrial morphology in both CF and CF expressing wt-CFTR cells, without affecting cell viability or mitochondrial membrane potential (ΔΨm). While individual treatments differentially modulated ROS production and ΔΨm, these effects were not statistically significant under combined treatment. These results highlight a previously unrecognized role for CFTR modulators in shaping mitochondrial morphology. A better understanding of these effects may reveal novel mechanisms underlying the regulation of mitochondrial structure and function. Full article

Background/Objectives: Cystoid macular lesion (CML) is a treatable cause of central vision loss in inherited retinal diseases (IRDs). We aimed to determine the frequency of CML in a large Hungarian IRD cohort and examine associations with causative genes. Methods: This longitudinal, retrospective, monocentric study included patients with genetically confirmed IRD identified from our database. Targeted next-generation sequencing (351-gene panel) and comprehensive ophthalmic evaluation were performed, including best-corrected visual acuity (BCVA) and spectral domain optical coherence tomography (SD-OCT). CML was defined as intraretinal hyporeflective spaces with well-defined borders visible on at least two B-scans within the SD-OCT macular volume and was categorized as cystoid macular edema (CME) or non-CME. Results: We enrolled 430 patients with genetically confirmed IRDs. CML was detected in 93 eyes of 57 patients. Mean age at OCT was 36.6 ± 18.7 years (range, 3–76); 32 were male (56.1%). Inheritance patterns were autosomal recessive in 24 (42.1%), X-linked in 19 (33.3%), and autosomal dominant in 14 (24.6%). Frequently implicated genes were RS1 (12/57), USH2A (7/57), NR2E3 (7/57), PRPF31 (4/57), RPGR (4/57), and RHO (4/57). CME predominated in retinitis pigmentosa (32/57, 56%), with mean BCVA 0.44 ± 0.29 (decimal) and central retinal thickness (CRT) 401 ± 181 µm. Non-CME CML occurred in 25/57 (44%)—notably in X-linked retinoschisis and enhanced S-cone syndrome—with BCVA 0.40 ± 0.23 and CRT 465 ± 258 µm. BCVA did not correlate with CRT (r_S = 0.18). Conclusions: CML occurred in 13.2% of patients within a large Hungarian cohort of genetically confirmed IRDs. Patients with IRD—mainly RP—are at higher risk for CML. Gene therapy is promising for retinal diseases, but CMLs can compromise effectiveness. Reducing and managing CME before gene therapy corroborates retinal stability and the functional state essential for the proper delivery and penetration of corrective genes to the target cells. Full article

Cystic fibrosis (CF) is an autosomal recessive genetic condition affecting nearly 1 in 4000 newborns. Early diagnosis and treatment have been shown to improve the care of individuals with CF, which is enhanced through newborn screening (NBS). The state of Florida has been performing CF NBS since 2007, and in 2022, Florida implemented enhanced next generation sequencing (NGS). The goal of this change was to identify individuals from under-represented racial and ethnic groups, who may have rare or de novo variants. NBS screening for CF involved a first tier with immunoreactive trypsinogen (IRT) ≥ 50 or the top 4% of daily specimens, whichever is lower, reflexing to a second tier. As of 2022, the second tier has evolved to an expanded sequence with an Agena 74-variant panel. Single variants would then reflex to the third tier utilizing NGS. NGS is able to confirm what is detected in second-tier testing, adding variants not included in the Agena panel, and refining the TG replications for Poly-T variants to determine pathogenicity of 5T results. When there is a variant of varying clinical consequence between the two databases, the most conservative classification is selected. Individuals with variants would then be referred to one of the contracted CF NBS referral centers for confirmatory sweat chloride testing (sweat). With implementation of NGS, referrals nearly tripled in 2022–2024, with 538 referrals in 2019; 485 in 2020; and 805 in 2021; followed by 1223 referrals made in 2022; 1146 in 2023; and 1294 in 2024. In 2022–2024, 71% of referrals to the contracted NBS CF referral centers were for single variant results, and no cases of CF were identified from these referrals. The number of CF cases remained about the same, ranging from 23 to 40 through the years 2019–2024. The number of CRMS/CFSPID cases, however, tripled going from 10 to 12 in 2019–2022 to over 100 in 2024. The reason for this change seems to be related to complex heterozygous genetic variants as opposed to abnormal sweat. Implementation of NGS for CF in Florida led to a significant increase in the identification of CFTR variants which affected all aspects of the NBS CF process, from an increased workload on the NBS laboratory and follow-up staff, to an increase in referrals to the NBS CF referral centers. The majority of referrals were for single-variant results, which meant the infants had a very low likelihood of having CF. It is recommended that when an algorithm involving NGS is utilized, one should verify that there are appropriate processes for sweat, including the manner in which single-variant CF results are handled, avoiding unnecessary healthcare utilization. Full article