Autosomal Recessive Mutation Research Articles

Effect of Intravenous Fluid Therapy in Managing Acute Painful Crises in Sickle Cell Disease Patients

Background: Sickle cell disease (SCD), an autosomal recessive mutation leading to alterations in the shape of red blood cells, compromises their oxygen-carrying capacity, and is prevalent in Saudi Arabia. Individuals with SCD experience vaso-occlusive crises, leading to severe pain episodes. Although fluid administration is a common practice to deter the sickling process, limited data exist on its efficacy. Method: This substudy was preplanned within the published randomized control trial titled \"Ketamine Administration for Acute Painful Sickle Cell Crisis: A Randomized Controlled Trial,\" conducted at King Fahad University Hospital in Saudi Arabia in 2019. Results: The analysis included 139 patients. Both arms received equal amounts and types of analgesics, with 51.7% receiving up to 500 ml intravenous fluid and 48.3% receiving more than 500 ml. Of the participants, 23.7% were admitted to the hospital, while 76.3% were discharged. The average length of stay in the emergency department (ED) was 4.6 ± 2.1 hours. There was no significant difference in the average pain score between the arms at 30-120 minutes. However, patients who received more fluid (> 500 ml) exhibited a higher admission rate and a longer ED stay. Conclusions: The amount of fluid administered to SCD patients in the emergency department during a vaso-occlusive crisis did not show a significant difference in pain score improvement. Notably, patients receiving more fluid demonstrated longer ED stays and higher admission rates.

Risdiplam as an orphan drug treatment of spinal muscular atrophy in adults and children (2 months or older)

ABSTRACT Introduction Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 (survival motor neuron1) and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a milder, slower progressing adult-onset type. The field of SMA treatment has changed significantly over the last years from being a nearly untreatable condition to the marketing of 3 new therapeutic options and the possibility to diagnose the disease very early through newborn screening. Areas covered This article covers and summarizes the published articles of preclinical and clinical data on risdiplam, a new oral centrally and peripherally distributed SMN2 pre-mRNA splicing modifier, together with reviews of abstract of important scientific meetings that have been organized over the past 4 years. Expert opinion The favorable efficacy/safety profile allows risdiplam to address remaining still unmet needs in the recent era of new SMA therapies. In particular, the possibility to administer risdiplam orally at home will make of it an attractive treatment option across all SMA phenotypes. Long-term efficacy and safety are still under evaluation.

The Launch of Two Sub-Studies of the Peak Registry, a Global, Longitudinal Study of Pyruvate Kinase Deficiency

Background: Pyruvate kinase (PK) deficiency is a rare, glycolytic enzymopathy caused by autosomal recessive mutations in the PKLR gene, which leads to lifelong hemolytic anemia and potentially serious complications such as extramedullary hematopoiesis, pulmonary hypertension, and iron overload. The Peak Registry (NCT03481738) was initiated in 2018 as a global, retrospective and prospective, observational study of pediatric and adult patients with a genetically confirmed diagnosis of PK deficiency to better understand the natural history, treatment patterns, and burden of disease. The registry aims to enroll 500 patients at approximately 60 sites in up to 20 countries over 7 years, with at least 2 and up to 9 years of follow-up. In 2021, two sub-studies were initiated to obtain additional information on the patient experience with PK deficiency, with a specific focus on 1) patient-reported health-related quality of life, including impact on work productivity and activity impairment (NCT04964323) and 2) the impact of PK deficiency on cognitive performance (NCT04995315). Unlike the core registry where data reporting is managed by sites via electronic case report forms, the sub-studies utilize an innovative decentralized design. The core registry and both sub-studies are currently open for enrollment. Methods: The design of the core registry has been previously described1. Both sub-studies are managed via a decentralized model using a web-based portal (N of 1 Health Research Platform; Digital Infuzion, Inc.). The patient-reported outcomes sub-study is open to adult (≥18 years) Peak participants in the US, Netherlands, Italy, Spain, and the UK with a target enrollment of 75 patients. Assessments include the PK Deficiency Diary (PKDD), PK Deficiency Impact Assessment (PKDIA), Functional Assessment of Cancer Therapy-Anemia (FACT-An, anemia subscale only), and the Work Productivity and Activity Impairment (WPAI) questionnaire. All assessments are completed electronically (computer, tablet, or mobile phone) at baseline and every 3 months thereafter (every 6 months for PKDD) over a 24-month period. The cognition sub-study is open to adult Peak participants in the US, Netherlands, and Italy with a target enrollment of 33 patients. Participants are required to use a desktop computer or laptop to complete a battery of self-administered cognitive assessments of psychomotor speed, attention, visual learning, and working memory utilizing the Cogstate Brief Battery (CBB). The assessments are completed at baseline and Day 90. Eligible patients can opt into sub-study participation through the platform's online Peak Patient Community Portal and begin the informed consent form (ICF) process which is managed by regional coordinating centers in each respective country. Once the ICF process has been completed, participants have access to the study surveys via the online portal. Data collected from both sub-studies will be summarized descriptively. Ethics approval has been received from all participating countries, and all stored data is de-identified. Results: Sites in the US were approved for sub-study enrollment on a rolling basis between July 2021 and May 2022, and had enrolled 5 patients as of 07Jul2022. Enrollment opened in Spain in April 2022, the Netherlands in May 2022, and in Italy and the UK in July 2022. As of 07Jul2022, 252 patients had enrolled in the core registry, of whom approximately 100 are adults in countries participating in the sub-studies and thus potentially eligible for sub-study participation. Summary: The Peak Registry provides a unique and impactful opportunity to enhance our understanding of PK deficiency. Two complementary sub-studies on health-related quality of life and cognition have recently been developed to obtain additional information on the patient experience with PK deficiency that has not been systematically captured or reported elsewhere. Further information is available at https://peakregistry.com and www.clinicaltrials.gov, and from medinfo@agios.com. 1Grace RF et al. Blood (2019) 134 (Supplement_1): 2223.

Sinusitis, otitis media and diffuse bronchiectasis in both lungs

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive or X-linked biallelic mutations inherited disease, characterized by motile cilia dysfunction. Typical manifestations include bronchiectasis, secretory otitis media, sinusitis, situs inversus, and infertility. PCD often needs to be differentiated from cystic fibrosis (CF) because of similar clinical manifestations. In this paper, a juvenile female who presented with recurrent cough and expectoration with fever since early childhood, had a history of secretory otitis media and sinusitis, and had been considered for the diagnosis of CF. After the discovery of compound heterozygous mutations in PCD related pathogenic genes by gene sequencing, combined with the clinical manifestations and imaging characteristics, PCD was finally diagnosed.

RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation

Epitranscriptomic regulation adds a layer of post-transcriptional control to brain function during development and adulthood. The identification of RNA-modifying enzymes has opened the possibility of investigating the role epitranscriptomic changes play in the disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is one of the few known brain-enriched methyltransferases able to methylate mammalian non-coding RNAs. NSun2 loss of function due to autosomal-recessive mutations has been associated with neurological abnormalities in humans. Here, we show NSun2 is expressed in adult human neurons in the hippocampal formation and prefrontal cortex. Strikingly, we unravel decreased NSun2 protein expression and an increased ratio of pTau/NSun2 in the brains of patients with Alzheimer’s disease (AD) as demonstrated by Western blotting and immunostaining, respectively. In a well-established Drosophila melanogaster model of tau-induced toxicity, reduction of NSun2 exacerbated tau toxicity, while overexpression of NSun2 partially abrogated the toxic effects. Conditional ablation of NSun2 in the mouse brain promoted a decrease in the miR-125b m6A levels and tau hyperphosphorylation. Utilizing human induced pluripotent stem cell (iPSC)-derived neuronal cultures, we confirmed NSun2 deficiency results in tau hyperphosphorylation. We also found that neuronal NSun2 levels decrease in response to amyloid-beta oligomers (AβO). Notably, AβO-induced tau phosphorylation and cell toxicity in human neurons could be rescued by overexpression of NSun2. Altogether, these results indicate that neuronal NSun2 deficiency promotes dysregulation of miR-125b and tau phosphorylation in AD and highlights a novel avenue for therapeutic targeting.

Nna1, Essential for Purkinje Cell Survival, Is also Associated with Emotion and Memory.

Nna1/CCP1 is generally known as a causative gene for a spontaneous autosomal recessive mouse mutation, Purkinje cell degeneration (pcd). There is enough evidence that the cytosolic function of the zinc carboxypeptidase (CP) domain at the C-terminus of the Nna1 protein is associated with cell death. On the other hand, this molecule's two nuclear localization signals (NLSs) suggest some other functions exist. We generated exon 3-deficient mice (Nna1N KO), which encode a portion of the N-terminal NLS. Despite the frameshift occurring in these mice, there was an expression of the Nna1 protein lacking the N-terminal side. Surprisingly, the pcd phenotype did not occur in the Nna1N KO mouse. Behavioral analysis revealed that they were less anxious when assessed by the elevated plus maze and the light/dark box tests compared to the control. Furthermore, they showed impairments in context-dependent and sound stimulus-dependent learning. Biochemical analysis of Nna1N KO mice revealed a reduced level of the AMPA-type glutamine receptor GluA2 in the hippocampal synaptosomal fraction. In addition, the motor protein kinesin-1, which transports GluA2 to dendrites, was also decreased. These results indicate that Nna1 is also involved in emotion and memory learning, presumably through the trafficking and expression of synaptic signaling molecules, besides a known role in cell survival.

The ADORA1 mutation linked to early-onset Parkinson’s disease alters adenosine A1-A2A receptor heteromer formation and function

Adenosine modulates neurotransmission through inhibitory adenosine A1 receptors (A1Rs) and stimulatory A2A receptors (A2ARs). These G protein-coupled receptors are involved in motor function and related to neurodegenerative diseases such as Parkinson’s disease (PD). An autosomal-recessive mutation (G2797.44S) within the transmembrane helix (TM) 7 of A1R (A1RG279S) has been associated with the development of early onset PD (EOPD). Here, we aimed at investigating the impact of this mutation on the structure and function of the A1R and the A1R-A2AR heteromer. Our results revealed that the G2797.44S mutation does not alter A1R expression, ligand binding, constitutive activity or coupling to transducer proteins (Gαi, Gαq, Gα12/13, Gαs, β-arrestin2 and GRK2) in transfected HEK-293 T cells. However, A1RG279S weakened the ability of A1R to heteromerize with A2AR, as shown in a NanoBiT assay, which led to the disappearance of the heteromerization-dependent negative allosteric modulation that A1R imposes on the constitutive activity and agonist-induced activation of the A2AR. Molecular dynamic simulations allowed to propose an indirect mechanism by which the G2797.44S mutation in TM 7 of A1R weakens the TM 5/6 interface of the A1R-A2AR heteromer. Therefore, it is demonstrated that a PD linked ADORA1 mutation is associated with dysfunction of adenosine receptor heteromerization. We postulate that a hyperglutamatergic state secondary to increased constitutive activity and sensitivity to adenosine of A2AR not forming heteromers with A1R could represent a main pathogenetic mechanism of the EOPD associated with the G2797.44S ADORA1 mutation.

Hedgehog pathway is negatively regulated during the development of Drosophila melanogaster PheRS-m (Drosophila homologs gene of human FARS2) mutants.

Hereditary spastic paraplegia (HSP) is a neurodegeneration disease, one of the reasons is caused by autosomal recessive missense mutation of the karyogene that encodes phenylalanyl-tRNA synthetase 2, mitochondrial (FARS2). However, the molecular mechanism underlying FARS2-mediated HSP progression is unknown. Mitochondrial phenylalanyl-tRNA synthetase gene (PheRS-m) is the Drosophila melanogaster homolog gene of human FARS2. This study constructed a Drosophila HSP missense mutation model and a PheRS-m knockout model. Some of the mutant fly phenotypes included developmental delay, shortened lifespan, wing-structure abnormalities and decreased mobility. RNA-sequencing results revealed a relationship between abnormal phenotypes and the hedgehog (Hh) pathway. A qRT-PCR assay was used to determine the key genes (ptc, hib, and slmb) of the Hh pathway that exhibited increased expression during different developmental stages. We demonstrated that Hh signaling transduction is negatively regulated during the developmental stages of PheRS-m mutants but positively regulated during adulthood. By inducing the agonist and inhibitor of Hh pathway in PheRS-m larvae, the developmental delay in mutants can be partly salvaged or postponed. Collectively, our findings indicate that Hh signaling negatively regulates the development of PheRS-m mutants, subsequently leading to developmental delay.

53 Nakajo-Nishimura syndrome: the first African case

Nakajo-Nishimura syndrome is a hereditary autoinflammatory disorder caused by an autosomal recessive homozygous mutation of the PSMB8 gene, which encodes the immunoproteasome subunit beta 5i. The clinical manifestations of NNS are mainly pernio-like skin rashes, nodular erythema, lipodystrophy, clubbed fingers, remittent fever, hepatosplenomegaly, and basal ganglia calcifications. Here we are reporting a case of NNS in an 11-year-old girl, who lives in eastern Algeria, born from a first-degree consanguineous marriage, she presented with erythematous patches on her face and her back, nodular erythema on her neck, swollen and painful fingers with acrocyanosis and recurrent fever that mainly occurred in cold weather. The patient received long-term treatment with low-dose glucocorticoids, along with immunomodulatory drugs (hydroxychloroquine with methotrexate), partial improvement clinically and biologically was observed. Colchicine was added to her treatment, with increased prednisone doses when she recently developed an AA amyloidosis. Our patient was diagnosed clinically with NNS because she exhibited six of the eight characteristics. To the best of our knowledge, this is the first case of NNS in Africa.

Mitochondrial Leukoencephalopathy in a One and Half-Year-old Boy

AbstractA one and half-year-old baby boy presented with subacute regression of milestones in all domains. On examination, he had spastic dystonic quadriparesis. Reflexes were brisk. Magnetic resonance imaging of the brain showed diffuse cavitating leukodystrophy involving bilateral periventricular white matter, centrum semiovale, and corona radiata. Magnetic resonance spectroscopy revealed a lactate peak and serum lactate levels were also elevated. Genetic studies revealed compound heterozygous autosomal recessive mutations in IBA57 gene. This case illustrates a rare mitochondrial encephalopathy called multiple mitochondrial dysfunction syndrome-3 caused by a novel IBA57 gene mutation.

VP.03 Diagnosing Titinopathy: lessons from a multi-omics pilot study

Titinopathy, or skeletal muscular dystrophy caused by autosomal recessive mutations in Titin (<i>TTN</i>), poses a unique diagnostic challenge because of A) significant variation in clinical manifestation, B) presence of rare putative deleterious <i>TTN</i> variants amongst healthy individuals which increases likelihood of incidental findings. Altogether, this makes establishing a definite diagnosis of Titinopathy based solely on phenotypic and genotypic information virtually impossible in the absence of corroborative evidence. We report six patients with Titinopathy from four unrelated families. In each case, prior genomics-based efforts had failed to reach a conclusive diagnosis and a confirmed diagnosis was reached by co-analyzing patient genomic and transcriptomic data. The multi-omics approach provided direct evidence confirming or dismissing impact of plausible candidate variants in TTN and other genes. This clarity of information was critical in solving these cases. The phenotypic diversity of the cohort highlights the diagnostic challenge. The first family included two siblings presented with adolescent onset multiple joint contractures, slowly progressive spine rigidity and elevated Creatine Kinase (CK). The severity of condition varied amongst the siblings with elder brother exhibited mild limb girdle weakness not seen in the younger sister. The second and third families comprise of a girl and boy respectively. Both unrelated patients had similar symptoms characterized by early onset hypotonia, delayed walking and elevated CK. Both had limb girdle muscle weakness and mild scoliosis. Their motor performance had been stable, and both continued to walk independently in adulthood. The fourth family included two siblings presented with arthrogryposis multiplex congenita and hypotonia after birth. Their mother reported decreased fetal movement during both pregnancies. Both elder sister and younger brother had delayed walking and limb girdle weakness. However, their joint contractures improved with age and regular stretching. The younger brother also had autistic features. Both siblings had normal CK. All patients in the study had normal echocardiogram suggesting lack of cardiac involvement. Our multi-omics findings link individualized patient condition to the specific functional impact of their implicated mutations.

The phenotypic spectrum of COX20-associated mitochondrial disorder.

In a recent article published in Brain, Dong and colleagues1 reported on a new cohort of eight Chinese patients primarily affected by sensory neuropathy with an onset age of between 1 and 17 years. Whole exome sequencing revealed pathogenic variants in the COX20 gene. Evidence of the underlying mitochondrial bioenergetic dysfunction complemented our knowledge that the COX20 protein is a mitochondrially located chaperone that aids the assembly of complex IV of the respiratory chain. Disease-causing COX20 variants were first reported in 2013 by Szklarczyk et al.,2 and to date, a total of 20 patients with autosomal recessive COX20 mutations have been published.3–7 Previous publications have typically reported infant-onset mitochondrial disorders with CNS involvement, characterized by growth retardation, hypotonia, dystonia and cerebellar ataxia; thus, the Dong et al.1 study significantly expanded the spectrum to include a milder phenotype that predominantly presents with sensorimotor axonal neuropathy. To add to this growing understanding of the COX20-associated mitochondrial disorder, we report a further seven unrelated Chinese patients.

A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition.

Fibulin-3 (F3 or EFEMP1) is a disulfide-rich, secreted glycoprotein necessary for maintaining extracellular matrix (ECM) and connective tissue integrity. Three studies have identified distinct autosomal recessive F3 mutations in individuals with Marfan Syndrome-like phenotypes. Herein, we characterize how one of these mutations, c.163T>C; p.Cys55Arg (C55R), disrupts F3 secretion, quaternary structure, and function by forming unique extracellular disulfide-linked homodimers. Dual cysteine mutants suggest that the C55R-induced disulfide species forms because of the new availability of Cys70 on adjacent F3 monomers. Surprisingly, mutation of single cysteines located near Cys55 (i.e., Cys29, Cys42, Cys48, Cys61, Cys70, Cys159, and Cys171) also produced similar extracellular disulfide-linked dimers, suggesting that this is not a phenomenon isolated to the C55R mutant. To assess C55R functionality, F3 knockout (KO) retinal pigmented epithelial (RPE) cells were generated, followed by reintroduction of wild-type (WT) or C55R F3. F3 KO cells produced lower levels of the ECM remodeling enzyme, matrix metalloproteinase 2, and reduced formation of collagen VI ECM filaments, both of which were partially rescued by WT F3 overexpression. However, C55R F3 was unable to compensate for these same ECM-related defects. Our results highlight the unique behavior of particular cysteine mutations in F3 and uncover potential routes to restore C55R F3 loss-of-function.

Partial human Janus kinase 1 deficiency predominantly impairs responses to interferon gamma and intracellular control of mycobacteria.

PurposeJanus kinase-1 (JAK1) tyrosine kinase mediates signaling from multiple cytokine receptors, including interferon alpha/beta and gamma (IFN-α/β and IFN-γ), which are important for viral and mycobacterial protection respectively. We previously reported autosomal recessive (AR) hypomorphic JAK1 mutations in a patient with recurrent atypical mycobacterial infections and relatively minor viral infections. This study tests the impact of partial JAK1 deficiency on cellular responses to IFNs and pathogen control.MethodsWe investigated the role of partial JAK1 deficiency using patient cells and cell models generated with lentiviral vectors expressing shRNA.ResultsPartial JAK1 deficiency impairs IFN-γ-dependent responses in multiple cell types including THP-1 macrophages, Epstein-Barr Virus (EBV)-transformed B cells and primary dermal fibroblasts. In THP-1 myeloid cells, partial JAK1 deficiency reduced phagosome acidification and apoptosis and resulted in defective control of mycobacterial infection with enhanced intracellular survival. Although both EBV-B cells and primary dermal fibroblasts with partial JAK1 deficiency demonstrate reduced IFN-α responses, control of viral infection was impaired only in patient EBV-B cells and surprisingly intact in patient primary dermal fibroblasts.ConclusionOur data suggests that partial JAK1 deficiency predominantly affects susceptibility to mycobacterial infection through impact on the IFN-γ responsive pathway in myeloid cells. Susceptibility to viral infections as a result of reduced IFN-α responses is variable depending on cell type. Description of additional patients with inherited JAK1 deficiency will further clarify the spectrum of bacterial and viral susceptibility in this condition. Our results have broader relevance for anticipating infectious complications from the increasing use of selective JAK1 inhibitors.

Therapeutic thoroughfares for adults living with Pompe disease.

Pompe disease is caused by autosomal recessive mutations in the acid α-glucosidase gene leading to a multiorgan deficiency of the enzyme acid glucosidase alfa. To recover to a nondiseased status, a lift over a threshold of 25% acid glucosidase alfa enzyme activity is required. This update on therapeutic thoroughfares for adult Pompe disease aims to assist neuromuscular and metabolic specialists. We reviewed the recent studies covering enzyme replacement therapy, gene therapy, and substrate reduction therapy in adult Pompe disease. Results of phase 3 studies and the first sets of long-term data of both novel enzyme replacement therapies, avalglucosidase alfa, and ciplaglucodsidase alfa combined with miglustat, are public. First gene therapy trials are ongoing. Substrate reduction therapy is in early transition to the clinical trial phase. We still miss dose escalation and intensification of frequency trials on enzyme replacement therapy in adults, probably suitable to echo current results in infantile and juvenile Pompe disease. Therapy of Pompe disease reaches new thoroughfares reducing the overall disease burden of patients; however, individualization of these novel therapeutic options remains challenging. Consensus-based and shared decision-based recommendations need to be established based on reliable real-world data to allow the best standards of care worldwide.

Novel RAB27A Variant Associated with Late-Onset Hemophagocytic Lymphohistiocytosis Alters Effector Protein Binding

Autosomal recessive mutations in RAB27A are associated with Griscelli syndrome type 2 (GS2), characterized by hypopigmentation and development of early-onset, potentially fatal hemophagocytic lymphohistiocytosis (HLH). We describe a 35-year old male who presented with recurrent fever, was diagnosed with Epstein-Barr virus-driven chronic lymphoproliferation, fulfilled clinical HLH criteria, and who carried a novel homozygous RAB27A c.551G > A p.(R184Q) variant. We aimed to evaluate the contribution of the identified RAB27A variant in regard to the clinical phenotype as well as cellular and biochemical function. The patient displayed normal pigmentation as well as RAB27A expression in blood-derived cells. However, patient NK and CD8+ T cell exocytosis was low. Ectopic expression of the RAB27A p.R184Q variant rescued melanosome distribution in mouse Rab27a-deficient melanocytes, but failed to increase exocytosis upon reconstitution of human RAB27A-deficient CD8+ T cells. Mechanistically, the RAB27A p.R184Q variant displayed reduced binding to SLP2A but augmented binding to MUNC13-4, two key effector proteins in immune cells. MUNC13-4 binding was particularly strong to an inactive RAB27A p.T23N/p.R184Q double mutant. RAB27A p.R184Q was expressed and could facilitate melanosome trafficking, but did not support lymphocyte exocytosis. The HLH-associated RAB27A variant increased Munc13-4 binding, potentially representing a novel mode of impairing RAB27A function selectively in hematopoietic cells.

The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects.

Familial hypercholesterolemia (FH) is an inherited disease characterized by reduced efficiency of low-density lipoprotein-cholesterol (LDL-C) removal from the blood and, consequently, an increased risk of life-threatening early cardiovascular complications. In Qatar, the prevalence of FH has not been determined and the disease, as in many countries, is largely underdiagnosed. In this study, we combined whole-genome sequencing data from the Qatar Genome Program with deep phenotype data from Qatar Biobank for 14,056 subjects to determine the genetic spectrum and estimate the prevalence of FH in Qatar. We used the Dutch Lipid Clinic Network (DLCN) as a diagnostic tool and scrutinized 11 FH-related genes for known pathogenic and possibly pathogenic mutations. Results revealed an estimated prevalence of 0.8% (1:125) for definite/probable cases of FH in the Qatari population. We detected 16 known pathogenic/likely pathogenic mutations in LDLR and one in PCSK9; all in a heterozygous state with high penetrance. The most common mutation was rs1064793799 (c.313+3A >C) followed by rs771019366 (p.Asp90Gly); both in LDLR. In addition, we identified 18 highly penetrant possibly pathogenic variants, of which 5 were Qatari-specific, in LDLR, APOB, PCSK9 and APOE, which are predicted to be among the top 1% most deleterious mutations in the human genome but further validations are required to confirm their pathogenicity. We did not detect any homozygous FH or autosomal recessive mutations in our study cohort. This pioneering study provides a reliable estimate of FH prevalence in Qatar based on a significantly large population-based cohort, whilst uncovering the spectrum of genetic variants associated with FH.

Three Siblings with Cohen Syndrome and a Novel Vacuolar Protein Sorting 13 Homolog B Mutation

Background: Cohen syndrome (CS) is caused by an autosomal recessive (AR) mutation of the vacuolar protein sorting 13 homolog B (VPS13B) gene on chromosome 8q22.2. It is characterized by hypotonia, obesity, prominent incisors, and mental retardation. It is diagnosed by the satisfaction of various systems of clinical diagnostic criteria. Molecular confirmation is by clinical exome sequencing. Clinical Description: We reported three siblings from a Kashmiri family with a positive history of consanguinity. The index case, a 26-month-old boy, was diagnosed with neutropenia during the workup for recurrent respiratory infections. He was also noted to have developmental delay, short stature, obesity, microcephaly, and facial dysmorphism. Retinitis pigmentosa was found. The diagnosis of CS was established on the detection of a pathogenic novel homozygous frameshift variant in the VPS13B gene. Evaluation of the family identified two other siblings, an 11-year-old boy and a 9-year-old girl, who satisfied the clinical criteria. Management and Outcome: The parents underwent genetic counseling. The affected children are under follow-up by a multidisciplinary team with regular monitoring of various parameters as per standard recommendations. Conclusion: Pediatricians should consider the application of diagnostic criteria of CS in a child with neutropenia, short stature, developmental delay, and microcephaly, if there is a setting of consanguinity. The diagnosis should be confirmed by genetic testing.

RWD25 Patient Characteristics and Healthcare Resource Utilization of Patients with Pyruvate Kinase Deficiency in a United States Electronic Health Record Database

Pyruvate kinase (PK) deficiency is a rare, inherited disorder caused by autosomal recessive mutations in the PKLR gene. There are no approved pharmacotherapies for PK deficiency. This study used data from a a large US electronic health record (EHR) database to summarize the clinical characteristics and healthcare resource use (HCRU) of patients with PK deficiency.

Primary familial brain calcification with mild phenotype due to a new PDGFB mutation

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder that presents cognitive and movement impairment. To diagnose PFBC, both brain calcium accumulations visible at computed tomography (CT) and autosomal dominant or recessive inherited genetic mutation(s) in one of the known genes have to be detected. We describe the case of a female patient aging 62, who presents marked calcifications at brain CT, not due to vitamin D deficiency. These data generated the suspect of PFBC. The patient has two young sons. The patient first, and her two sons later, underwent clinical and neurological examinations, brain CT, and blood draw for genetic analysis at our clinic. Patient's neurological exams detected gait impairment and tremor of the hands. Brain CT showed calcification of the basal ganglia, cerebellar dentate nuclei, and white matter. Laboratory exams identified high serum parathormone (PTH) and low plasmatic levels of vitamin D; supplementation with vitamin D normalized PTH values. Genetic analysis of the known PFBC-causing genes uncovered a new pathogenic mutation in PDGFB. The same calcifications and genetic variant were found in her younger son. Our report presents the case of a patient mildly affected by PFBC due to a novel PDGFB mutation that could have been mistaken with hyperparathyroidism if any further investigations had not been performed. Her younger asymptomatic son bore the same calcification and mutation of the mother, highlighting the importance of family pedigree collection and early diagnosis for prevention of symptoms' onset with future treatments.