Autosomal Recessive Condition Research Articles

Pulmonary alveolar microlithiasis: A case report.

An uncommon autosomal recessive condition called pulmonary alveolar microlithiasis (PAM) is characterized by the buildup of intra-alveolar calcifications inside the lung parenchyma. In this case report, a 16-year-old female patient with PAM is examined in-depth clinically and radiologically. The patient's radiographs revealed dense consolidation in both lungs. The diagnosis of PAM was confirmed by high-resolution computed tomography (HRCT), which showed bilateral, extensive and symmetrical distribution of the calcifications. We go over PAM's clinical presentation, imaging traits, diagnostic difficulties, and current therapeutic strategies. In order to provide a complete overview of this uncommon lung illness, we also evaluate relevant research.

Pilot study of paediatric regional lung function assessment via X-ray velocimetry (XV) imaging in children with normal lungs and in children with cystic fibrosis

IntroductionCystic fibrosis (CF) is a life-limiting autosomal recessive genetic condition. It is caused by mutations in the gene that encodes for a chloride and bicarbonate conducting transmembrane channel. X-ray velocimetry...

Hyaline Fibromatosis Syndrome Diagnosed by Whole Genome Sequencing

Hyaline fibromatosis syndrome is an extremely rare autosomal recessive condition caused by biallelic pathogenic variants in the ANTXR2 gene that leads to abnormal growth of hyalinized fibrous tissue. Severity ranges from life-threatening intractable diarrhea, recurrent infection, and acute pain to milder disease resulting in skin lesions and less severe contractures. Here, we report the case of a 3-month-old female who presented with joint contractures and severe pain followed by failure to thrive. Diagnosis via ultra-rapid whole genome sequencing allowed our team to provide appropriate care and anticipatory guidance for this patient and family.

Long-term clinical outcomes and management of hypertriglyceridemia in children with Apo-CII deficiency

Background and aimAPO CII, one of several cofactors which regulate lipoprotein lipase enzyme activity, plays an essential role in lipid metabolism. Deficiency of APO CII is an ultra-rare autosomal recessive cause of familial chylomicronemia syndrome. We present the long-term clinical outcomes of 12 children with APO CII deficiency. Methods and resultsThe data of children with genetically confirmed APO CII deficiency were evaluated retrospectively. Twelve children (8 females) with a mean follow-up of 10.1 years (±3.9) were included. At diagnosis, the median age was 60 days (13 days-10 years). Initial clinical findings included lipemic serum (41.6%), abdominal pain (41.6%), and vomiting (16.6%). At presentation, the median triglyceride (TG) value was 4341 mg/dL (range 1277–14,110). All patients were treated with a restricted fat diet, medium-chain triglyceride (MCT), and omega-3-fatty acids. In addition, seven patients (58.3%) received fibrate. Fibrate was discontinued in two patients due to rhabdomyolysis and in one patient because of cholelithiasis. Seven (58.3%) patients experienced pancreatitis during the follow-up period. One female experienced recurrent pancreatitis and was treated with fresh frozen plasma (FFP). ConclusionsApo CII deficiency is an ultra-rare autosomal recessive condition of hypertriglyceridemia associated with significant morbidity and mortality. Low-fat diet and MCT supplementation are the mainstays of therapy, while the benefit of TG-lowering agents are less well-defined.

Aromatase deficiency due to novel CYP19A1 mutation: a rare cause of maternal and fetal virilization

Abstract Objectives Aromatase deficiency is a rare autosomal recessive condition due to a mutation in the CYP19A1 encoding aromatase enzyme. This enzyme protects the fetus and mother from excess androgens by converting them into estrogen. We are reporting a case of aromatase deficiency presented with atypical genitalia and maternal virilization due to a novel mutation in CYP19A1. Case presentation A 10-day-old newborn presented with atypical genitalia and a history of maternal virilization during pregnancy. On examination, the baby had a Prader score of 3. Further investigation revealed karyotype 46 XX, with a normal uterus and ovaries on ultrasonography. The hormonal profile of the baby was normal except for the raised follicle stimulating hormone (FSH). Maternal ultrasound revealed polycystic ovaries, and the hormonal profile was within the normal range with slightly raised testosterone. Whole exome sequencing was done, which reported that the baby was carrying a novel homozygous mutation of the CYP19A1 gene c.575G>C p. (Arg192Pro), confirming the diagnosis of aromatase deficiency. Conclusions Aromatase deficiency is a rare condition. A history of maternal virilization during pregnancy in a child born with atypical genitalia should alert physicians to consider aromatase deficiency.

Pathogenic and likely pathogenic germline variation in patients with myeloid malignancies and their unrelated HLA-matched hematopoietic stem cell donors

Aims: The revised 2022 World Health Organization classification recognizes myeloid neoplasms with associated germline predisposition as a defined subcategory, underscoring the clinical significance of likely pathogenic (LPV) and pathogenic (PV) germline variation in these diseases. To better understand the role of LPV/PV in blood or marrow transplants (BMT), a curative therapy for myeloid neoplasms, we measure their frequency and association with mortality in two cohorts of donor-recipient pairs. Methods: LPV/PV frequencies in 665 cancer-related genes were measured using exomechip genotyping data in 1990 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and their unrelated donors, registered with the Center for International Blood and Marrow Transplant Research. Cox proportional hazard models were used to test variant association with recipient mortality one-year post-transplant. Results: Thirteen autosomal dominant (AD) LPV/PV in eight genes were found in 2.8% of patients and 2.2% of donors; those linked to autosomal recessive conditions appeared in 11.1% of patients and 11% of donors. The most common AD LPV/PV mutations in recipients were found in DDX41 (n = 18). For donors, the most frequent AD PVs occurred in CHEK2 (n = 21) and Fanconi Anemia (FA) genes (n = 7). DDX41 and CHEK2 variation did not correlate with patient survival, but patients with donors with an LPV/PVs in an FA gene had lower survival (HR = 2.38, 95%CI: 1.06-5.31, P = 0.035) than patients whose donors did not have an FA LPV/PV. Conclusion: We identified LPVs/PVs in cancer genes in donors and recipients and are the first to show an association of donor FA PVs with mortality after BMT.

Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology

Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.

Detection of a novel gross deletion in the UNC13D gene ends the diagnostic odyssey for a family with familial hemophagocytic lymphohistiocytosis 3

BackgroundFamilial hemophagocytic lymphohistiocytosis (FHL) is an immunological disorder characterized by overactivation of macrophages and T lymphocytes. This autosomal recessive condition has been characterized into multiple types depending on the genetic etiology. FHL type 3 is associated with bi-allelic pathogenic variants in the UNC13D gene.Case presentationWe present a 12-year diagnostic odyssey for a family with FHL that signifies the advances of FHL genetic testing in a clinical genetic diagnostic laboratory setting. We describe the first case of a large UNC13D gross deletion in trans to a nonsense variant in a family with FHL3, which may have been mediated by Alu elements within introns 12 and 25 of the UNC13D gene.ConclusionsThis case highlights the importance of re-evaluating past genetic testing for a patient and family as test technology evolves in order to end a diagnostic odyssey.

Carrier frequency estimation of pathogenic variants of autosomal recessive and X-linked recessive mendelian disorders using exome sequencing data in 1,642 Thais

BackgroundPeople with autosomal recessive disorders often were born without awareness of the carrier status of their parents. The American College of Medical Genetics and Genomics (ACMG) recommends screening 113 genes known to cause autosomal recessive and X-linked conditions in couples seeking to learn about their risk of having children with these disorders to have an appropriate reproductive plan.MethodsWe analyzed the exome sequencing data of 1,642 unrelated Thai individuals to identify the pathogenic variant (PV) frequencies in genes recommended by ACMG.ResultsIn the 113 ACMG-recommended genes, 165 PV and likely PVs in 60 genes of 559 exomes (34%, 559/1642) were identified. The carrier rate was increased to 39% when glucose-6-phosphate dehydrogenase (G6PD) was added. The carrier rate was still as high as 14.7% when thalassemia and hemoglobinopathies were excluded. In addition to thalassemia, hemoglobinopathies, and G6PD deficiency, carrier frequencies of > 1% were found for Gaucher disease, primary hyperoxaluria, Pendred syndrome, and Wilson disease. Nearly 2% of the couples were at risk of having offsprings with the tested autosomal recessive conditions.ConclusionsBased on the study samples, the expanded carrier screening, which specifically targeted common autosomal recessive conditions in Thai individuals, will benefit clinical outcomes, regarding preconception/prenatal genetic carrier screening.

An Unusual Case of Kartagener’s Syndrome with Fertility

Abstract Situs inversus, chronic sinusitis, and bronchiectasis together make up the trinity that characterize the uncommon autosomal recessive genetic ciliary condition known as Kartagener’s syndrome. The fundamental issue is the improper movement of cilia, which causes infertility, frequent chest infections, and ear, nose, and throat complaints. A fertile male with Kartagener’s disease is a unique case of this rare entity, which we are reporting here. The significance of having a high index of suspicion in such patients cannot be stressed to arrive at an early diagnosis and, whenever possible, provide alternatives for fast treatment and avoid needless symptom evaluation.

Unusual Presentation of Congenital Chloride Diarrhea Mimicking Colovesical Fistula: A Case Report and Literature Review

Background: Congenital Chloride Diarrhea (CCD) is a rare autosomal recessive condition characterized by lifelong watery diarrhea. CCD is challenging to diagnose because of its severe clinical presentations and differentials. Therefore, it is crucial to be diagnosed early and receive appropriate management as it causes early death if left untreated or due to complications. Case Report: A Saudi newborn baby boy who was passing a large amount of urine through the anal canal and was otherwise healthy. He was referred to our center with a high suspicion of a colovesical fistula. Diagnosed with CCD by exclusion of fistula after confirmation with contrast study. Conclusion: This case highlights an unusual presentation of CCD mimicking a colovesical fistula. To our knowledge, no similar case has been reported in the literature, and we believe this is the first Saudi case report. It underscored the diagnostic challenges of this rare disorder and emphasized the importance of early recognition and accurate diagnosis to prevent such complications.

Unusual presentation of congenital chloride diarrhea mimicking colovesical fistula: a case report and literature review

Background: Congenital chloride diarrhea (CCD) is a rare autosomal recessive condition characterized by lifelong watery diarrhea. CCD is challenging to diagnose because of its severe clinical presentations and differentials. Therefore, it is crucial to be diagnosed early and receive appropriate management as it causes early death if left untreated or due to complications. Case Report: A Saudi newborn baby boy was passing a large amount of urine through the anal canal and was otherwise healthy. He was referred to our center with a high suspicion of a colovesical fistula. Diagnosed with CCD by the exclusion of fistula after confirmation with contrast study. Conclusion: This case highlights an unusual presentation of CCD mimicking a colovesical fistula. To the best of our knowledge, no similar case has been reported in the literature, and we believe this is the first Saudi case of CCD mimicking a colovesical fistula. It underscored the diagnostic challenges of this rare disorder and emphasized the importance of early recognition and accurate diagnosis to prevent such complications.

Phenylketonuria (PKU): Causes, classifications, clinical symptoms, diagnosis and treatment

The autosomal recessive condition phenylketonuria (PKU) is brought on by mutations in the gene that codes for phenylalanine hydroxylase (PAH). Phenylalanine (Phe) builds up in the blood as a result of PAH mutations. Untreated PKU can result in several dangers, including brain damage. Due to factors including enhanced genetic testing and newborn screening, the number of PKU patients is predicted to rise. Therefore, it is necessary to popularize the knowledge of PKU in the society. Additionally, minimizing the occurrence of PKU symptoms is greatly aided by early identification and treatment of PKU. In this context, this review highly summarizes all aspects of knowledge about KPU, focusing on the genetic cause, classification, clinic symptoms, diagnosis, and treatment. Newborn screening and related diagnostic technologies, including the Guthrie test, the McCaman and Robins fluorescence assay, and Tandem mass spectrometry, are introduced in this paper. The dietary measures, PKU Formula, and two effective medications, Kuvan and Palynzio, are involved as well. In addition, state-of-the-art genetic techniques for diagnosis and treatment are also included. With an earlier and more accurate diagnosis, governments around the world should strengthen awareness of PKU and lead to the development of effective diagnostics and therapeutics. Finally, the purpose of this paper is to let more people know about PKU, strive for early detection and treatment, and do everything possible to avoid the occurrence of phenylketonuria symptoms.

First preimplantation genetic testing case of Meckel syndrome with a novel homozygous TXNDC15 variant in a non-consanguineous Chinese family.

Meckel-Gruber syndrome (MKS) is a perinatally lethal, genetically heterogeneous, autosomal recessive condition caused by defective primary cilium formation. So far, the association of TXNDC15-related MKS has been reported in only five independent families from diverse ethnic origins, including Saudi, Pakistani, Estonian, and Indian. Here, we report a fetus diagnosed with MKS at 12 weeks, exhibiting typical ultrasound findings. Low-coverage whole-genome sequencing was used to identify chromosomal abnormalities. Trio-base whole exome sequencing (trio-WES) was performed to investigate the potential pathogenic variants associated with MKS. Preimplantation genetic testing for monogenic disorders (PGT-M) was applied to prevent the transmission of the pathogenic variant. A novel homozygous pathogenic variant in the TXNDC15 gene was identified through trio-WES. The application of PGT-M successfully prevented the transmission of the pathogenic variant and resulted in an ongoing pregnancy. This is the first report of a TXNDC15 variant in the Chinese population and the first PGT case of TXNDC15-related MKS worldwide. The successful application of PGT-M in this family provides a potential approach for other monogenic diseases. Our case expands the variant spectrum of TXNDC15 and contributes to the molecular diagnosis and genetic counseling for MKS. This case underscores the importance of appropriate genetic testing methods and accurate genetic counseling in the diagnosis of rare monogenic diseases.

Diagnostic accuracy and the first genotype-phenotype correlation in glycogen storage disease type V.

Glycogen storage disease type V (GSDV) is an autosomal recessive metabolic condition caused by pathogenic PYGM variants. This is an underdiagnosed condition as it presents with exercise intolerance in children. We reviewed the GSDV cases of a tertiary hospital center to assess diagnostic timing/accuracy, as well as potential clinical/analytical predictors of such factors. We retrospectively reviewed all GSDV cases with follow-up in both Pediatric and Adult Metabolic Diseases consultations. We included 28 cases and assessed their hospital record for clinical information. Over 90% of our cases had late diagnoses, with more than 50% being diagnosed in adulthood despite symptom onset in preschool (very late diagnosis). Diagnostic age was lower in patients exhibiting myoglobinuria. Interestingly, patients with a positive family history of GSDV had similar rates of very late diagnoses, likely since the index case was already detected very late in life. Finally, we observe that the R50* variant is associated with increased myoglobinuria and CK elevation, in a dosage-dependent manner. We concluded that GSDV is severely underdiagnosed, and that some clinical and analytical aspects of the condition can be more indicative of this diagnosis. Furthermore, we propose for the first time a genotype-phenotype correlation in GSDV. GSDV is a pediatric-onset metabolic disorder that is mostly diagnosed late in the adult age and commonly misdiagnosed. We observed the first genotype-phenotype correlation in GSDV, regarding the common R50* variant. Awareness of GSDV for pediatricians and the overall medical community is vital.

Improved recognition of lung function decline as signal of cystic fibrosis pulmonary exacerbation: a Cystic Fibrosis Learning Network Innovation Laboratory quality improvement initiative

IntroductionCystic fibrosis (CF) is a systemic autosomal recessive condition characterised by progressive lung disease. CF pulmonary exacerbations (PEx) are episodes of worsening respiratory status, and frequent PEx are a risk...

#322 : A Rare Case Report of Successfull Live Twin Birth in a Couple Who are Carriers of Mucopolysaccharidoses VII-Sly Syndrome

Introduction: Mucopolysaccharidoses VII or sly syndrome is an autosomal recessive condition discovered in 1972 by William Sly, occurs due to mutation in the beta glucoronidase encoding gene, it is an ultra-rare neurometabolic disorder caused by inherited deficiency of the lysosomal enzyme [Formula: see text]eta-glucuronidase. Precise data regarding its epidemiology is scarce, but birth prevalence is estimated to vary from 0.02 to 0.24/100,000 live births with 54 types of recorded mutations. The clinical course and disease progression are widely heterogeneous. So far 9 pregnancies have been recorded in patients with sly syndrome of which the majority showed some deformity. Here we present a case of a couple with two different variants of GUSB gene who delivered live twin birth with normal development. Background: A couple aged 29 & 31 who were anxious to conceive came to the clinic with a previous history of two abortions for pre conceptual counselling. Both pregnancies had features suggestive of non-anemic type nonimmune hydrops with increased nuchal fold thickness in USG. Both her pregnancies were terminated mid trimester with the autopsy results conclusive of the findings. Method & Results: Whole exome sequencing showed that both were carriers of GUSB gene of two different variants encoding for Sly syndrome. Based on the WES and karyotyping reports genetic counselling was given, and PGT-M was suggested. The patient underwent antagonist protocol and 12MII were retrieved. ICSI was done and the embryos were cultured to day 5 and subjected to PGT-A, PGT-M. The resultant 2 carrier blastocysts were transferred. Post transfer Beta Hcg was positive. The patient had an uneventful obstetric course and delivered normal twin girl babies on 27/01/23. The twins showed no physical abnormality and their genetic profiling showed they were carriers of GUSB gene. Conclusion: This case demonstrates that with appropriate pre-conceptual evaluation, genetic counselling, constant maternal and fetal surveillance, carriers of sly syndrome can be given multidisciplinary care leading to successful outcome.

Whole Exome Sequencing of Patients with Adult-Onset Evans Syndrome: A Cohort of 80 Patients

Introduction Loss of tolerance toward several self-antigens suggests an underlying genetic predisposition. A previous study (1) conducted in children with Evans syndrome revealed a high prevalence of pathogenic mutations in genes involved in primary immunodeficiencies. Whether these findings are restricted to children is unknown. In this study, we assessed the prevalence of constitutional genetic variants in a cohort of patients with adult onset Evans syndrome. Patients and methods We consecutively included from November 2021 to June 2023 patients that had been diagnosed with adult onset (≥18 years) Evans syndrome (association of immune thrombocytopenia (ITP), warm autoimmune hemolytic anemia (wAIHA) and/or autoimmune neutropenia (AIN) according to international guidelines (2,3)), and identified in France throughout the network of the national reference center for adult' autoimmune cytopenia. We excluded patients with a systemic lupus (according to Systemic Lupus International Collaborating Clinics criteria (4)), and patients with indolent B cell malignancies at Evans syndrome onset. Clinical and biological data were retrospectively collected using a standardized form. Patients underwent whole-exome sequencing after written and informed consent was obtained. Gene variants already published and/or with in vitro confirmed consequences were considered as genetic diagnoses. Clinical interpretation of variants was performed according to the ACMG guidelines (5). A patient was classified as having a genetic diagnosis if carryinghemizygous/heterozygous pathogenic or likely pathogenic variant (for X-linked or autosomal dominant conditions), or 2 pathogenic or likely pathogenic variants in the same gene (for autosomal recessive conditions). Results We identified 80 patients (40% female, median age 31 years at Evans syndrome diagnosis [range 18-76]) with adult-onset Evans syndrome from 19 centers. Median age at first cytopenia was 28 years [range 1-73], and 13 patients (16%) were under 18 years at first cytopenia. 78 patients (96%) had ITP (chronic in 87%), 59 (73%) had wAIHA (with at least one relapse in 58%), and 38 (47%) had AIN (chronic in 74%). Median delay between first and second cytopenia was 18 months (range 0 - 329) and 28 patients (35%) had synchronous onset of cytopenia. Twenty-four patients (30%) had associated immune manifestation (involving endocrine system in 9%, lung in 9%, gastrointestinal tract in 6%, skin in 5%, central nervous system in 4%) and 28% had antinuclear antibody titers ≥ 1/160. Lymphoproliferation was found in 56%, including lymphadenopathy in 41% and splenomegaly in 35%. Nine patients (11%) had lymphoma or cancer history. Twenty patients (25%) had humoral immune defect, including 13 (16%) with a common variable immunodeficiency (CVID)-like phenotype. In the whole cohort, 9 patients (11.25%) had a genetic diagnosis that could be linked to Evans syndrome, with heterozygous variants in CTLA4, STAT3, NFKB1, CYBB, TNFAIP3, DDX41, MYH9 and homozygous variant in PIK3CG. Twenty (25%) patients had genetic testing prior to this study (targeted Sanger sequencing [N=3], or NGS panel [N=17]), resulting in 2 genetic diagnoses ( CYBB and TNFAIP3). A family history of immune manifestations in first-degree relatives was found in 56% of the patients with genetic diagnosis versus 20% of patients without (P=0.0308). However, the proportion of patients with CVID-like phenotype, associated immune disorder, lymphoproliferation, cancer/lymphoma, positive antinuclear antibodies, or pediatric onset of first cytopenia was not significantly increased in patients with genetic diagnosis. Discussion As expected, the proportion of genetic diagnoses in patients with adult onset Evans syndrome was lower that what was previously described in children, but led to a significant impact on clinical management in some patients. We did not find clinical or biological features associated with a genetic diagnosis, suggesting that genetic testing should be considered in every adult patient diagnosed with Evans syndrome in the absence of any obvious underlying cause or condition. References (1) Hadjadj J et al., Blood 2019; 134: 9-21. (2) Provan D et al., Blood Adv 2019; 3: 3780-817. (3) Jäger U et al., Blood Rev 2020; 41: 100648. (4) Petri M et al., Arthritis Rheum 2012; 64: 2677-86. (5) Richards S et al., Genet Med 2015; 17: 405-24.

Bioinformatics Analysis Identifies Potential Hub Genes, Therapeutic Agents and Crucial Pathways in the Pathogenesis of Refsum Disease

Refsum Disease is a infrequent, inherited, autosomal recessive condition. The purpose of this study was to investigate prospective therapeutic drugs to cure Refsum disease and to determine the critical genes/pathways through bioinformatics analysis. Using the text mining method, Refsum disease-related genes were discovered and MCODE plugin, GO & KEGG analyses was used to examine modules. A PPI network was created by STRING and visualized in Cytoscape. Drug-gene interactions were investigated using the drug-gene interaction database. Using the text mining of gene (TMG) method, 64 distinct genes in Homo sapiens linked to Refsum illness. There were 71 edges and 48 nodes in a PPI network. 13 hub node genes were discovered using a cluster analysis of filtering nodes. The genes were then significantly elevated in protein trans-membrane transport, protein import to the peroxisome matrix and fatty acid beta-oxidation, according to the enrichment analysis. We discovered that two already-approved medications could target two of the 13 chosen genes. The findings revealed the hub genes for Refsum illness to be SLC27A2, AGXT, GNPAT, CRAT, HSD17B4, AMACR, CAT, SCP2, PEX13, PEX10, PEX1, PEX7, and PEX2. Additionally, Ibuprofen and alcohol were named as prospective therapeutic agents for the management and therapy of Refsum’s illness. Only bioinformatics tools were used in this study further in-vitro and in-vivo studies are required because phenotypic differences will vary from person to person depending on the expressivity of the gene.

Congenital myasthenic syndrome type 2C in a neonate: Redefining the phenotype of CHRNB1‐related myasthenic syndromes

AbstractObjectiveWe present a neonate with generalized weakness due to autosomal recessive congenital myasthenic syndrome type 2C (CMS2C) resulting from a compound heterozygous mutation in the CHRNB1 gene.Patient descriptionOur patient was determined by multiple methodologies to have a diagnosis of CMS2C (OMIM #616314). Whole‐genome sequencing revealed two distinct variants in the CHRNB1 gene (OMIM *100710): a maternally inherited 2 kb pathogenic microdeletion on chromosome 17p13.1 and a paternally inherited intronic deletion (c.1218‐9_1218‐7) that was reported by the laboratory as a variant of unknown significance.ConclusionsCMS2C is a rare autosomal recessive genetic condition associated with early‐onset muscle weakness. Our patient had a paternally inherited deletion in CHRNB1 (c.1218‐9_1218‐7) that was initially described as a variant of unknown significance. We suggest this finding is “likely pathogenic,” as this aberration has not been commonly described. He also had a partial deletion of CHRNB1 in the maternally inherited allele, which provides further evidence that partial gene deletions may be a more common molecular mechanism than previously known for this condition. The combination of the clinical presentation and electrophysiologic data allowed us to understand the molecular findings and ultimately diagnose CMS2C in our patient.