Autosomal Recessive Mode Research Articles

Molecular and Clinical Characterization of a Cohort of Autosomal Recessive Sensorineural Hearing Loss in Egyptian Patients

Hearing loss (HL) is one of the most common health problems worldwide. Autosomal recessive non-syndromic sensorineural hearing loss (ARNSHL) represents a large portion of congenital hereditary HL. Our study was conducted on 13 patients from 13 unrelated families. The majority of patients presented with congenital severe to profound bilateral sensorineural HL. All patients were subjected to detailed family history and three-generation pedigree analysis to exclude any environmental cause and to ensure an autosomal recessive mode of inheritance. Molecular analysis was performed using the whole exome sequencing (WES) technique for the recruited patients. Three variants in the MYO7A and OTOF genes were reported for the first time in patients with ARNSHL (one nonsense, one frameshift, and one splice variant). Ten previously reported variants were detected in seven genes (GJB2, MYO15A, BSND, OTOF, CDH23, SLC26A4, and TMIE). They varied between missense, nonsense, frameshift, and splice variants. This study expands the molecular spectrum of two types of autosomal recessive deafness (types 2 and 9).

Masks of Albinism: Clinical Spectrum of Hermansky–Pudlak Syndrome

Hermansky–Pudlak syndrome (HPS) is a rare disease inherited in the autosomal recessive mode, including 11 clinical genetic subtypes. They are associated with impaired function of the BLOC protein complex (Biogenesis of Lysosome-related Organelles Complexes), and the subunits of the AP-3 complex (adaptor protein complex). Each has its own clinical features, but they are all characterized by albinism, bleeding disorder, and visual abnormalities. Eleven patients from eight unrelated families with an incoming diagnosis of albinism were examined and novel and previously described genetic variants in HPS1, HPS6, and BLOC1S6 genes (types HPS1, HPS6, and HPS9) were found. To determine the optimal therapy and recommendations for further follow up, it is necessary to consider the entire clinical spectrum and genetic polymorphism of the disease. An interdisciplinary approach, combined with the use of non-routine diagnostic techniques such as RNA analysis, is essential for achieving accurate diagnoses in certain complex cases.

Socio-Demographic, Epidemiological and Clinical Pattern of the Egyptian Children with Cystic Fibrosis

Abstract Background Cystic fibrosis (CF) is a genetic disease; most definitely serious, transmitted in am autosomal recessive mode, that mainly affects the respiratory and gastrointestinal system. However, little is known about the characteristics of CF among the Egyptian children. Aim of the Work To record the demographic, clinical characteristics, diagnostic tools, the most frequent mutations and the outcome of the Egyptian cystic fibrosis children attending our center, paving the way for having national survey of CF children. Patients and Methods This was a cross-sectional studywhich was conducted at Pediatric Pulmonology Unit, Ain Shams University, Children’s Hospital for a period of 12 month recruiting CF patients attending Pediatric Pulmonology Clinic during their routine visits. Results Ninety-six CF patients were included whose ages was 6.44(±4.33) years, and ranged between 0.5 to 17.7 years. Gender distribution was fairly even, with 52.1% males and 47.9% females. Most lived in rural areas (56.3%), while 43.8% were in urban areas. 75% of the patients were of average socioeconomic status. A significant portion had a family history of cystic fibrosis (74%). Diverse initial complaints among participants were reported where the most common was failure to thrive in 30.22% of patients, followed by steatorrheain 29.17%. Recurrent chest infections affected 25% of patients, while delayed passage of meconium was reported in 7.3%. The most common presenting symptoms were cough (96.9%) followed by steatorrhea(92.7%) followed by expectoration(84.4%) and wheezes 81.3%. The most common genetic mutations wasF508del (30.2%) No mortality has been reported among the studied cystic fibrosis patients Conclusion the comprehensive data presented in this study provide a thorough understanding of the clinical profile, most common mutations and outcomes of the 96 pediatric patients with CF in a single center which is recommended to be done in all centers caring for CF patients to allow establishment of CF registry in Egypt

Biallelic TYR and TKFC variants in Egyptian patients with OCA1 and new expanded TKFC features

BackgroundOculocutaneous albinism type1 (OCA1) is caused by the TYR gene's homozygous and compound heterozygous variants. TKFC gene variants cause triokinase & FMN cyclase deficiency syndrome with variable multisystemic disorders.ObjectivesTo determine the potential disease-causing variants in two deceased patients presenting atypical OCA1 features by demonstrating three generations for a single family. The two deceased neonates had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy. We also explored the potential mechanisms for the causative relationship between TKFC and multisystem disorders.Patients and methodsDue to the new emerging symptoms that weren’t reported before with the TYR gene, the following methods were performed: Sanger sequencing for the TYR gene, followed by whole exome sequencing, co-segregation, and computational analyses.ResultsExtensive parental consanguinity was found, and consequently an autosomal recessive mode of inheritance was prioritized. Upon performing sequencing and segregation data, the following has been confirmed: positive co-segregation of nonsense homozygous NM_000372.5:c.346C > T p.(Arg116*) variant in TYR gene and multisystem disease-missense homozygous NM_015533.4:c.598G > A p.(Val200Ile) variant in TKFC gene in the two affected index patients who deceased due to hypertrophic cardiomyopathy. Using computational analysis, we found that c.598G > A p.(Val200Ile) pathogenicity has led to the failure of L2-K1 active site closure due to the potential differential fluctuation between valine and isoleucine residues. Subsequently, disruption of endogenous DHA phosphorylation was found. Two potential mechanisms exploring the causative relationship between TKFC gene and multisystem disorders have been suggested.ConclusionsThis study presented a first family with the co-existence of biallelic variants in TYR and TKFC genes associating severe skeletal abnormalities and lethal hypertrophic cardiomyopathy. Neither of these genes would have been pursued in the standard genetic counseling. Such discovery is paving the way for more efficient genetic counseling. Comparing TKFC results with literature data showed that our relevant expanded TKFC variant is the 3rd worldwide.

Genetic investigation of patients with autosomal recessive ataxia and identification of two novel variants in the SQSTM1 and SYNE1 genes

Hereditary ataxias are classified by inheritance patterns into autosomal dominant, autosomal recessive, X-linked, and mitochondrial modes of inheritance. A large group of adult hereditary ataxias have autosomal dominant inheritance, and autosomal recessive cerebellar ataxias (ARCAs) are rare, with greater diversity in phenotypic and genotypic features. Therefore, comprehensive genetic testing is useful for identifying the genes responsible for ARCAs. We identified two novel pathogenic variants of the SQSTM1 and SYNE1 genes via whole-exome sequencing in patients with ARCAs.

Clinical, Laboratory, Molecular, and Reproductive Aspects of Combined Deficiency of Factors V and VIII.

Congenital combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D, OMIM 227300) is a rare hereditary coagulopathy and accounts for approximately 3% of cases of rare coagulation disorders. The prevalence of this disease in the general population is estimated to be 1:1,000,000 and is significantly higher in regions where consanguineous marriages are permitted, such as the Mideast and South Asia. The disease has an autosomal recessive mode of inheritance and therefore occurs with an equal incidence among males and females. Heterozygous mutation carriers usually do not have clinical manifestations. The molecular basis of this disease differs from that of stand-alone congenital deficiencies of FVIII and FV. F5F8D is caused by mutations in either LMAN1 or MCFD2, which encode components of a cargo receptor complex for endoplasmic reticulum to Golgi transport of FV and FVIII, leading to defects in an intracellular transport pathway shared by these two coagulation factors. Congenital combined deficiency of FV and FVIII is characterized by decreased activities of both FV and FVIII in plasma, usually to 5 to 30% of normal. Clinical manifestations in most cases are represented by mild or moderate hemorrhagic syndrome. The simultaneous decreases of two coagulation factors present complications in the diagnosis and management of the disease. In female patients, the disease requires a special approach for family planning, pregnancy management, and parturition. This review summarizes recent progress in clinical, laboratory, and molecular understanding of this disorder.

Whole Genome Analysis in Consanguineous Families Reveals New Loci for Speech Sound Disorder (SSD).

Speech is the most common means of communication in humans. Any defect in accurate speech production ability results in the development of speech sound disorder (SSD), a condition that can significantly impair an individual's academic performance, social interactions, and relationships with peers and adults. This study investigated the genetic basis of SSD in three Pakistani families. We performed family-based genome-wide parametric linkage analysis and homozygosity mapping in three consanguineous families with SSD from the Punjab province of Pakistan. The Test for Assessment of Articulation and Phonology in Urdu (TAAPU) was used to analyze the speech articulation data and determine the Percentage Correct Consonants (PCC) score. The PCC score defined the affected and unaffected individuals in each family. Parametric linkage analysis revealed a linkage to chromosome 5 (5q21.3-5q23.1) with a significant logarithm of the odds (LOD) score of 3.13 in a Pakistani family with specific language impairment-97 (PKSLI-97) under an autosomal recessive mode of inheritance. The other two families showed a suggestive linkage at 6p22.1, 14q12, and 16q12.1 under the recessive mode of inheritance. Interestingly, homozygosity mapping showed a loss of heterozygosity in the linkage region at 5q15-5q23.1, shared among seven affected (mostly in the younger generation) and one unaffected individual of PKSLI-97. Our analysis identified the 6p22 locus previously implicated in dyslexia, childhood apraxia of speech (CAS), and language impairment, confirming the role of KIAA0319 and DCDC2 in this locus. These findings provide statistical evidence for the genomic regions associated with articulation disorder and offer future opportunities to further the role of genes in speech production.

NFS-04. GENETIC COUNSELLING IN A MULTI-TUMOR PREDISPOSITION SYNDROME: A NOVEL FOUR-GENERATION TUNISIAN PEDIGREE

Abstract BACKGROUND Cancer predisposition syndromes associated with an increased risk of CNS tumors and colorectal polyposis are heterogeneous inherited disorders associated with multiples genes. The delineation of the inheritance pattern and the management of the genetic testing are recommended for optimal care of patients and their families. Our aim was to report a cancer predisposition brain tumor-polyposis syndrome in a four-generation Tunisian consanguineous pedigree characterized by uncommon tumors localizations. METHODS The index case was a 43-year-old infertile woman presented to our genetic counselling because of a suspected familial cancer predisposition syndrome. She consulted for digestive symptoms with epigastralgia. Six adenomatous polyposis of the colon were confirmed histologically. Her sister died of colon cancer at the age of 50. She developed a malignant mesenteric recurrence after surgical resection of a moderately differentiated adenocarcinoma infiltrating the meso fat with lymph node metastases. Their three sisters and brother did not have any cancer. From the same third generation, only one cousin died of a brain cancer identified as a glioblastoma at the age of 43. Their maternal grandmother and her two brothers died of respectively breast, laryngeal and urothelial cancers. The second generation and fourth generation involved healthy members. RESULTS Analysis of the pedigree of this family indicated an autosomal recessive mode of inheritance of the brain tumor-polyposis syndrome. Clinically, there was uncommon association with breast, laryngeal and urothelial cancers in the first generation and brain/colon cancers in the third generation. CONCLUSIONS A recessive multi-tumor predisposition syndrome related to high microsatellite instability resulting in a mismatch repair deficiency seems to be the most reliable diagnosis in this family. Familial NTHL1 tumor and MUTYH associated polyposis syndromes were also suspected. NGS-based testing, from whole exome sequencing to multigene panel testing, is suggested as the most accurate genetic testing in such heterogeneous multi-tumor predisposition syndromes.

A Novel Ectodysplasin a Gene mutation of X-Linked Hypohidrotic Ectodermal Dysplasia.

Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that influences structures of ectodermal origin, such as teeth, hair, and sweat glands. Compared with autosomal recessive and dominant modes of inheritance, the X-linked HED (XLHED) characterized by Hypodontia/Oligodontia teeth, Absent/sparse hair, Anhidrosis/hypohidrosis, and characteristic facial features, is the most frequent and its primary cause is the mutation of ectodysplasin A (EDA) gene. This research aimed to expound the clinical and molecular features of a Chinese male with XLHED and to summarize and compare several previous findings. Genomic DNA was obtained from the peripheral blood of the proband and his family members, then Sanger sequencing was used to perform a mutational analysis of EDA. Real-time quantitative PCR and Western blotting were used to detect EDA expression. The transcriptional activity of NF-κB was detected using a luciferase assay. The probandwith XLHED was identified a novel EDA mutation, c.1119G>C(p.M373I), that affected the molecular analysis of transmembrane protein exon8 mutations, inherited from the mother. He showed a severe multiple-tooth loss, with over 20 permanent teeth missing and sparse hair and eyebrows, dry, thin, and itching skin. Furthermore, his sweating function was abnormal to a certain extent. The functional study showed that this novel mutant led to a significant decrease in the EDA expression level and transcriptional activity of NF-κB. Our findings extend the range of EDA mutations in XLHED patients, which provides the basis and idea for further exploring the pathogenesis of XLHED.

ALS-associated VRK1 R321C mutation causes proteostatic imbalance and mitochondrial defects in iPSC-derived motor neurons

Vaccinia-related kinase 1 (VRK1) is a gene which has been implicated in the pathological process of a broad range of neurodevelopmental disorders as well as neuropathies, such as Amyotrophic Lateral Sclerosis (ALS). Here we report a family presenting ALS in an autosomal recessive mode of inheritance, segregating with a homozygous missense mutation located in VRK1 gene (p.R321C; Arg321Cys). Proteomic analyses from iPSC-derived motor neurons identified 720 proteins eligible for subsequent investigation, and our exploration of protein profiles revealed significant enrichments in pathways such as mTOR signaling, E2F, MYC targets, DNA repair response, cell proliferation and energetic metabolism. Functional studies further validated such alterations, showing that affected motor neurons presented decreased levels of global protein output, ER stress and downregulation of mTOR signaling. Mitochondrial alterations also pointed to decreased reserve capacity and increased non-mitochondrial oxygen consumption. Taken together, our results present the main pathological alterations associated with VRK1 mutation in ALS.

Clinical profile of children with metabolic liver diseases presenting in a tertiary care hospital of Eastern India

Clinical profile of children with metabolic liver diseases presenting in a tertiary care hospital of Eastern India

Clinicopathological and pedigree investigation of a novel spinocerebellar neurological disease in juvenile Quarter Horses in North America.

In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. Twelve neurologically affected QH foals and the dams. Genomic DNA was isolated and pedigrees were manually constructed. All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs <1 month of age in North America that is etiologically distinct from other clinically similar neurological disorders. Once the causative variant for EJSCA is validated, carriers can be identified through genetic testing to inform breeding decisions.

Mutation of the Thap4 gene causes dwarfism and testicular anomalies in rats and mice.

The petit (pet) locus is associated with dwarfism, testicular anomalies, severe thymic hypoplasia, and high postnatal lethality, which are inherited in autosomal recessive mode of inheritance in rats with a Wistar strain genetic background. Linkage analysis localized the pet locus between 98.7Mb and 101.2Mb on rat chromosome 9. Nucleotide sequence analysis identified 2bp deletion in exon 2 of the Thap4 gene as the causative mutation for pet. This deletion causes a frameshift and premature termination codon, resulting in a truncated THAP4 protein lacking approximately two-thirds of the C-terminal side. Thap4 is expressed in various organs, including the testis and thymus in rats. To elucidate the biological function of THAP4 in other species, we generated Thap4 knockout mice lacking exon 2 of the Thap4 gene through genome editing. Thap4 knockout mice also exhibited dwarfism and small testis but did not show high postnatal lethality. Thymus weights of adult Thap4 knockout male mice were significantly higher compared to wild-type male mice. Although Thap4 knockout male mice were fertile, their testis contained seminiferous tubules with spermatogenesis and degenerative seminiferous tubules lacking germ cells. Additionally, we observed vacuoles in seminiferous tubules, and clusters of cells in the lumen in seminiferous tubules in Thap4 knockout male mice. These results demonstrate that spontaneous mutation of Thap4 gene in rats and knockout of Thap4 gene in mice both cause dwarfism and testicular anomalies. Thap4 gene in rats and mice is essential for normal testicular development, maintaining spermatogenesis throughout the entire region of seminiferous tubules.

The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population

BackgroundTo investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children’s Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry.MethodsWe selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS).ResultsOur study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes.ConclusionsIran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

Особенности патологии органа зрения при орфанном синдроме Pierson вследствие мутации гена LAMB2 у детей: обзор литературы и клиническое наблюдение

Pierson syndrome is an orphan disease with an autosomal recessive mode of inheritance, characterized by combined pathology of the organ of vision, kidneys and central nervous system. Pierson syndrome is caused by a mutation in the LAMB2 gene, mapped on chromosome 3p21, encoding β2-laminin. The pathology of the organ of vision in Pierson syndrome in children is quite diverse. They are characterized by the presence of cataract, posterior lenticonus, iris hypoplasia, glaucoma, retinal detachment, etc. Microcoria (pupil diameter less than 2 mm) is also often observed due to atrophy of the pupillary dilator. The final diagnosis of Pierson syndrome can only be made based on the results of a molecular genetic study. Due to the severe lifethreatening renal manifestations of Pierson syndrome, for a long time the description of ophthalmological pathology was rather superficial. However, considering the high frequency and clinical severity of vision pathology in Pierson syndrome, it seems especially important to study in detail the features of the ocular phenotype in this disease. We have described a clinical observation of a child with Pierson syndrome, who was diagnosed with a missense mutation of the LAMB2 gene, a previously undescribed variant (rs143405268) in exon 18. The disease manifested itself as a combined pathology of the organ of vision, kidneys and the central nervous system. The ocular phenotype of the probands represented by microcoria, diffuse congenital cataract, and later by secondary glaucoma (after cataract surgery). Features of the renal phenotype of the proband were revealed – a horseshoe-shaped kidney, proteinuria not reaching the level of nephrotic syndrome, with preserved renal function. The peculiarity of this case of a child with Pierson syndrome is the absence of nephrotic syndrome in combination with the classic ocular phenotype with a previously undescribed variant of the LAMB2 gene mutation identified. Key words: pierson syndrome, LAMB 2, congenital cataract, microcoria, secondary glaucoma

NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. We investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20. Neither of the investigated overexpression lines completely rescued the lethality upon knockdown of the endogenous ND-20. However, a partial rescue was found upon overexpression of wildtype NDUFS7, where pupal lethality was moved to later developmental stages, which was not seen upon canine mutant overexpression, thus providing additional evidence for the pathogenicity of the identified variant. Our results show the potential of the fruit fly as a model for canine disease allele validation and establish NDUFS7:p.(Val179Met) as causative variant for the investigated canine Leigh syndrome.

Missing Heritability in Albinism: Deep Characterization of a Hungarian Albinism Cohort Raises the Possibility of the Digenic Genetic Background of the Disease.

Albinism is characterized by a variable degree of hypopigmentation affecting the skin and the hair, and causing ophthalmologic abnormalities. Its oculocutaneous, ocular and syndromic forms follow an autosomal or X-linked recessive mode of inheritance, and 22 disease-causing genes are implicated in their development. Our aim was to clarify the genetic background of a Hungarian albinism cohort. Using a 22-gene albinism panel, the genetic background of 11 of the 17 Hungarian patients was elucidated. In patients with unidentified genetic backgrounds (n = 6), whole exome sequencing was performed. Our investigations revealed a novel, previously unreported rare variant (N687S) of the two-pore channel two gene (TPCN2). The N687S variant of the encoded TPC2 protein is carried by a 15-year-old Hungarian male albinism patient and his clinically unaffected mother. Our segregational analysis and in vitro functional experiments suggest that the detected novel rare TPCN2 variant alone is not a disease-causing variant in albinism. Deep genetic analyses of the family revealed that the patient also carries a phenotype-modifying R305W variant of the OCA2 protein, and he is the only family member harboring this genotype. Our results raise the possibility that this digenic combination might contribute to the observed differences between the patient and the mother, and found the genetic background of the disease in his case.

Ectopia Lentis in Three Successive Generations: A Case Series Study

Aim: To describe the clinical profiles of patients of three successive generations of a Bangladeshi family affected by familial ectopia lentis. Methods: A case series study was conducted in a tertiary eye hospital in Bangladesh from 2015 to 2019. We evaluated twentythree people of the same family of three successive generations. Among them, thirteen patients were affected by familial ectopia lentis. Several patients from all three generations underwent elaborate general examinations to rule out systemic and metabolic disorders. Results: Among thirteen patients, eleven had bilateral Ectopia lentis. Among six adult patients, three had bilateral cataracts. ICCE was done on one patient from 2nd generation (pedigree 7) in another eye hospital. The other two patients (Pedigree-2 and 9) were blind; among seven child patients, four developed cataracts. One was visually significant and underwent PPL with AVT (Pedigree-14). Visual rehabilitation was done with aphakic glass. The other three children had cataracts but not in the pupillary area - not visually significant. No systemic associations were found except one who was suspected of Marfan syndrome. Conclusions: Not only many patients in one family but also the occurrence in three generations is exceptional for Ectopia Lentis Syndrome. The autosomal recessive mode was found in other studies, but this family pedigree analysis favoured an autosomal dominant inheritance. Emphasis is needed on the importance of regular follow-up and management.

Unraveling the genome: Familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an inherited, autoinflammatory disease with a high prevalence in Middle Eastern and Mediterranean populations including Turks, Iranian, Spanish, Sephardic Jews, Arabs, and other Mediterranean ethnic groups. Autoinflammatory diseases are genetically predetermined disorders with multisystem effects primarily caused by defects in innate immunity. Although primarily known for an autosomal recessive mode of inheritance, there are increasing case reports associated with single Mediterranean fever (MEFV) mutation or dominant transmission. There have been over 300 variants identified in the MEFV gene; however, roughly 9-11 variants are responsible for the phenotypical expression seen with FMF. Symptoms include recurrent episodes of fever of unknown origin, abdominal, chest, or joint pain because of serosal inflammation. Persistent elevations in serum amyloid A can lead to complications like renal amyloidosis, kidney dysfunction, and end-stage kidney disease. Familial Mediterranean fever is diagnosed clinically using the Tel-Hashomer criteria and confirmed through genetic testing. Treatment includes initiation of colchicine with the goal of stopping attacks and preventing renal dysfunction and end-stage kidney disease. Genetic testing helps to identify the specific mutation allowing the provider to create a patient-specific treatment plan, monitor for complications such as renal amyloidosis, and enhance knowledge on the genetic heterogeneity and possible epigenetic factors.

Monoallelic Pathogenic Variants in Hemophagocytic Lymphohistiocytosis Genes Are Uncommon and Not Associated with Hematopoietic Cell Transplantation Outcomes in Severe Aplastic Anemia

Introduction: Severe aplastic anemia (SAA) is primarily an immune-mediated disease, but a subset of patients have a germline genetic predisposition. Germline genetic testing for patients with SAA is recommended to guide patient treatment, including adjustment for hematopoietic cell transplantation (HCT) modalities. Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hyperinflammatory condition often associated with cytopenias. HLH etiology is genetically variable with X-linked or autosomal recessive (XLR or AR) modes of inheritance. The role of monoallelic pathogenic/likely pathogenic (P/LP) variants in recessive HLH-associated genes in SAA etiology or outcomes is unclear. In this study, we determined the frequency of monoallelic HLH-associated gene variants in a large cohort of patients with acquired SAA and evaluated their association with HCT outcomes. Methods: The Transplant Outcomes in Aplastic Anemia (TOAA) project is a collaboration between the NCI and the Center for International Blood and Marrow Transplant Research and consists of genomic and clinical data from 824 patients with SAA who received HCT between 1989-2015. We excluded 140 patients with inherited bone marrow failure syndrome (92 with a clinical diagnosis and 48 genetically identified; McReynolds, Blood, 2022). We used exome sequencing data from the remaining 684 non-inherited SAA patients and used ACMG/AMP criteria to curate variants in 14 HLH-associated genes (AR: PRF1, UNC13D, STX11, STXBP2, ITK, CD27, LYST, RAB27A, AP3B1, BLOC1S6, SLC7A7; and XLR: XIAP, SH2D1A, MAGT1). Variants were deemed deleterious variants of uncertain significance (del-VUS) if there were damaging predictions in &amp;gt;3/5 in-silico meta-predictors (BayesDel, REVEL, CADD, MetaSVM and EIGEN). Follow-up started at the day of HCT and ended at outcome of interest, death, loss to follow-up, or end of study period (August 2017). We used the Kaplan-Meier estimator to calculate the probability of overall survival (OS) after HCT, using a log-rank test for statistical comparisons. For other HCT outcomes, we used cumulative incidence calculator accounting for competing risk of death. Results: There were 57 HLH variants in 49 of the 684 (7.2%) patients: 17 variants present in 19 patients (2.8%) were pathogenic or likely pathogenic (P/LP) and 40 were del-VUS. Eight of 17 P/LP variants were loss of function (3 frameshift, 3 splice site loss, and 2 nonsense). Among the 19 patients with P/LP variants, 16 (84%) had monoallelic variants in genes with AR inheritance, and PRF1 was the most frequently affected (in 8/19 patients). The median age at HCT was comparable in patients with (median=20 years; range=5-62) and without (median=20 years; range=0.2-77) P/LP HLH variants. We did not observe statistically significant differences in other demographics or transplant-related factors in the two groups, except for a higher frequency of male in patients with P/LP variants (79% vs. 55%, in those with and without HLH variants, respectively; p=0.04). All patients with P/LP HLH variants achieved neutrophil engraftment by day 30 compared with 92% of patients without HLH variants. The cumulative incidence of neutrophil engraftment at day 20 was 89%, 95% CI=70-99% for patients with HLH variants and 64%, 95% CI=60-67% in those without variants (p=0.01) (Figure 1A). No statistically significant associations between HLH variants and other key HCT outcomes were noted (p&amp;gt;0.05). The 5-year OS probability in all patients with P/LP variants was 89% (95% CI=72-99) compared to 66% (95% CI=63-70) in those without variants (p=0.06) (Figure 1B). When restricting the analysis to patients receiving reduced intensity/non-myeloablative regimen, the 5-year OS was 92% (95% CI=72-100%) in those with P/LP HLH variants versus 75% (95% CI=70-79%) in those without variants. Conclusions: We found that 7.2% of patients undergoing HCT for acquired SAA carried potentially deleterious variants in HLH genes, with 2.8% carrying a P/LP variant. HCT outcomes in patients with monoallelic P/LP variants was similar to those without P/LP HLH variants. Our data suggest that identification of monoallelic P/LP variants in HLH genes does not influence HCT outcomes, and no special treatment consideration, other than that used for SAA, is warranted.