Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.

PPFIBP1 encodes for the liprin-ß1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies.

PURPOSE: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. METHODS: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. RESULTS: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. CONCLUSION: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.

The morbid genome of ciliopathies: an update.

PURPOSE: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. METHODS: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. RESULTS: In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. CONCLUSION: In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.

Autozygome and high throughput confirmation of disease genes candidacy.

PURPOSE: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. METHODS: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. CONCLUSIONS: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.

Musculoskeletal symptoms among radiologists in Saudi Arabia: a multi-center cross-sectional study.

BACKGROUND: Musculoskeletal symptoms account for the majority of work-related illnesses resulting in a significant economic burden on society. Computer users are subject to unique repetitive strains that predispose them to musculoskeletal symptoms. In the digitalized field of radiology, radiologists spend long hours interpreting medical images on computers. This study aimed to determine the prevalence of musculoskeletal symptoms among radiologists in Saudi Arabia and their contributing factors. METHODS: An online survey was sent to radiologists in all hospitals (academic, public and private) in the major cities of the Eastern Province of Saudi Arabia covering demographic characteristics, workload (e.g. the time spent at a computer workstation), and workstation environments including the number of monitors as well as the adjustability of the height of the workstation and the viewing distance. This survey of 263 radiologists was conducted in April 2019. It included an evaluation of musculoskeletal symptoms using the Nordic Musculoskeletal Questionnaire. The study outcome was the presence of disabling musculoskeletal symptoms in any body region, which restricted the performance of normal activities in the last 12 months. Results were analyzed descriptively using a Chi-square test and logistic regression analysis to estimate the odd ratio of experiencing disabling musculoskeletal symptoms in the last 12 months. RESULTS: The survey was completed by 198 participants (111 men and 87 women) with a response rate of 75.3%. Most participants (71.2%) were aged below 40 years. A multivariate logistic regression analysis revealed being a female radiologist (OR = 2.7; 95% CI: 1.2-6.5), aged 30-39 years (OR = 4.1; 95% CI: 1.1-15.3), and predominantly reviewing computed tomography (CT) images (OR = 4.1; 95% CI: 1.4-12.3) or ultrasound scans (OR = 5.9; 95% CI: 1.4-25.3) were associated with higher prevalence of disabling musculoskeletal symptoms, compared to those aged below 30 years and those who reviewed various imaging modalities, respectively. CONCLUSIONS: Musculoskeletal symptoms are common among radiologists with lower back and neck pain being the most frequent complaints. Being a female radiologist, aged 30-39 years, and reviewing CT or ultrasound scans were associated with higher rates of disabling musculoskeletal symptoms.

Progressive deafness-dystonia due to SERAC1 mutations: A study of 67 cases.

OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.

Genetic Influence in Developmental Dysplasia of the Hip in Saudi Arabian Children Due to GDF5 Polymorphism.

Developmental dysplasia of the hip (DDH) is quite common among Saudi Arabian babies. With an objective to assess the presence of SNP rs143383 and the alleles in the GDF5 gene among patients with DDH, parents, and unaffected siblings, we undertook this case-controlled study. We collected and analyzed for a functional single nucleotide polymorphism (SNP) in the 5'-untranslated region of the GDF5 gene (rs143383), 473 blood samples, (100 patients, 200 parents, 73 siblings and 100 healthy controls. We determined the association between the patients' genotype and their fathers', mothers' and siblings' genotype through Chi-square analysis. The majority of those screened possessed the TC genotype, and 61.8% of patients and their fathers had the TT genotype. There was no association between patients' and fathers' genotype, P value < 0.332, 95% CI (0.328-0.346), and between patients' and mothers', P < 0.006, 95% CI (0.004-0.007). When considering DDH patients' and the control group's genotypes, the odds ratios of TT versus other combined (0.641 > 1) and CC versus other combined (0.474 < 1) revealed that the TT genotype has higher risk of developing DDH compared with the CC genotype. The 95 percent confidence interval of TT versus other combined and CC versus other combined is 0.932-2.891 and 0.208-1.078, respectively. For patients' and fathers' genotypes, the odds ratios of TT versus other combined (1.275 > 1) and CC versus other combined (0.815 < 1) indicate that the TT genotype has higher risk of exhibiting DDH compared to the CC genotype. For patients' and siblings' genotypes, the odds ratios of TT versus other combined (1.669) and CC versus other combined (1.048) specify that the TT genotype possesses higher risk of developing DDH compared with the CC genotype. Our study shows that there exists a relationship between GDF5 (SNP rs143383) and DDH in our population. Second, we found for the first time that the genotype TT and the T allele were overly expressed in the patients and the fathers. More studies on the confirmation of this genetic marker for DDH are called for.

Serial Post-Operative Radiographs in Surgically Managed Pediatric Supracondylar Humeral Fractures: Are They Always Required?

Objective:  Supracondylar humeral fractures are among the most common pediatric fractures that require surgical intervention when displaced. Recent attention has been directed towards the utilization of serial radiographs in the post-operative period and their effect on decision-making. This study aimed to determine the usefulness of postoperative radiographs early post-operatively, with the goal of determining the optimal frequency for these radiographs. Methods: Pediatric patients who sustained a supracondylar humeral fracture and underwent operative intervention over a 15-year period were included in this study. Data were collected, including the baseline characteristics of the patients, fractures, and operative interventions. In addition, the time until healing, the total number of X-rays before K-wire removal, and postoperative function were evaluated. Results: A total of 122 pediatric patients were included, with a mean age of 5.33 ± 2.93 years. Most fractures were Gartland Type III (74.6%). Most fractures healed at 4 (36.1%) and 3 weeks (35.2%) after surgery. Of the cohort, 94.3% underwent four different x-rays before wire removal, with 4.9% requiring revision surgery. All revision cases were Gartland type 3, and for all cases, the decision to revise was made within three weeks of surgery. Conclusion: Routine post-fixation radiography should not be performed for surgically treated supracondylar humeral fractures before healing. An exception is the Gartland type 3 fracture, for which earlier imaging may be indicated.

Parental Beliefs and Attitudes Toward the Use of Baby Walkers in the Eastern Region of Saudi Arabia.

Background Baby walkers (BWs) are popular among parents worldwide, despite safety concerns and developmental impact concerns, as they are influenced by cultural beliefs, social myths, and personal interests. This study aims to assess parental beliefs and attitudes toward the use of BWs in the Eastern region of Saudi Arabia. Materials and methods A descriptive cross-sectional study was conducted among 400 mothers in the Eastern region of Saudi Arabia. Data were collected through an online questionnaire, which included demographic information, BW usage, reasons for usage/non-usage, and awareness of the dangers and disadvantages of BWs. Descriptive statistics and chi-square tests were used for data analysis. Results Among the participants, 332 (83.0%) reported using BWs for their children. The majority of parents i.e. 237 parents (71.3%) used walkers for their child's fun and 146 parents (43.9%) used them for 1-2 hours daily. Among the reasons for non-usage, concerns about affecting the child's walking and potential injuries were most common in 29 (42.6%) and 28 (41.1%) parents, respectively. Significant associations were found between mother's age, child's birth order, age of crawling, age of independent walking, and BW usage. Forty-eight children (14.4%) who used walkers experienced injuries, including falling downstairs 20 (41.6%) and flipping over on a flat surface 21 (43.7%). Conclusion This study highlights the prevalence of BW usage and the reasons behind parental decisions in the Eastern region of Saudi Arabia. While many parents use BWs to promote early walking and provide entertainment, concerns about safety and potential developmental impacts persist.

Assessing Acetabular Index Angle in Infants: A Deep Learning-Based Novel Approach.

Developmental dysplasia of the hip (DDH) is a disorder characterized by abnormal hip development that frequently manifests in infancy and early childhood. Preventing DDH from occurring relies on a timely and accurate diagnosis, which requires careful assessment by medical specialists during early X-ray scans. However, this process can be challenging for medical personnel to achieve without proper training. To address this challenge, we propose a computational framework to detect DDH in pelvic X-ray imaging of infants that utilizes a pipelined deep learning-based technique consisting of two stages: instance segmentation and keypoint detection models to measure acetabular index angle and assess DDH affliction in the presented case. The main aim of this process is to provide an objective and unified approach to DDH diagnosis. The model achieved an average pixel error of 2.862 ± 2.392 and an error range of 2.402 ± 1.963° for the acetabular angle measurement relative to the ground truth annotation. Ultimately, the deep-learning model will be integrated into the fully developed mobile application to make it easily accessible for medical specialists to test and evaluate. This will reduce the burden on medical specialists while providing an accurate and explainable DDH diagnosis for infants, thereby increasing their chances of successful treatment and recovery.

Time of surgery and surgeon level in supracondylar humerus fractures in pediatric patients: A retrospective study.

BACKGROUND: Supracondylar humerus fractures account for more than 60% of all elbow fractures and about 1/5 of all pediatric fractures. Unfortunately, these fractures can be associated with risk of complications including neurovascular injuries, malunions and limb deformities. Controversy exists regarding the effect of time of surgical intervention and/or level of surgeon performing the surgery on outcome of these fractures. AIM: To determine whether time of surgical intervention and/or surgeon level influence the outcomes of surgically managed pediatric supracondylar humerus fractures. METHODS: We retrospectively studied 155 pediatric patients presenting with a supracondylar humerus fracture in a level 1 trauma center from January 2006 to December 2019. The data extracted included demographic data, fracture characteristics, surgical data, and follow-up outcomes. The collected data was analyzed and P values of < 0.05 were considered statistically significant. RESULTS: Of the cohort, 11% of patients had documented post-operative complications, of which the majority occurred in surgeries performed after day time working hours and in fractures requiring open reduction. While the lowest complication rate was found in surgeries performed by pediatric orthopaedic surgeons, this did not reach statistical significance. CONCLUSION: In pediatric patients undergoing surgery for supracondylar fractures, we found a higher complication rate when surgeries were not performed during working hours. Surgeon level and training had no significant effect on the risk of post-operative complications.

Family-base rare variant association analysis in Saudi Arabian hydrocephalus subjects using whole exome sequencing.

BACKGROUND: Hydrocephalus is a highly heterogeneous multifactorial disease that arises from genetic and environmental factors. Familial genetic studies of hydrocephalus have elucidated four robustly associated hydrocephalus associated loci. This study aims to identify potential genetic causation in cases of hydrocephalus, with or without spina bifida and Dandy Walker Syndrome (DWS), using family-based rare variant association analysis of whole exome sequencing. METHODS: We performed whole exome sequencing in 143 individuals across 48 families where at least one offspring was affected with hydrocephalus (N.=27), with hydrocephalus with spina bifida (N.=21) and with DWS (N.=3), using Illumina HiSeq 2500 instrument. RESULTS: No pathogenic or putative pathogenic single-nucleotide variants were evident in the four known hydrocephalus loci in our subjects. However, after examining 73 known hydrocephalus genes previously identified from literature, we identified three potentially impactful variants from the cohort. Using a gene panel comprising variants in known neural tube defects loci, we identified a total of 1024 potentially deleterious variants, of which 797 were missense variants and 191 were frameshift variants, 36 were stop gain/loss variants. A small portion of our family pedigree analyses yielded putative genetic signals which may be responsible for hydrocephaly elated phenotypes, however the low diagnostic yield may be due to lack of capture of genetic variants in the exonic regions i.e. structural variants may only be evident from whole genome sequencing. CONCLUSIONS: We identified three potentially impactful variants from our cohort in 73 known hydrocephalus genes previously identified in literature.

BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

A review of polydactyly and its inheritance: Connecting the dots.

OBJECTIVE: This study collects what is known about the inheritance underpinnings of syndromic and non-syndromic polydactylies and highlights dactyly presentations with unknown genetic roots. This review summarizes the current information and genetics-enhanced understanding of polydactyly. BACKGROUND: There is a frequency of 0.37 to 1.2 per 1000 live births for polydactyly, which is also known as hyperdactyly. It is characterized by the presence of extra fingers. Polydactyly is caused by a failure in limb development, specifically the patterning of the developing limb bud. The phenotypic and genetic variability of polydactyly makes its etiology difficult to understand. Pre-axial polydactyly, central polydactyly (axial), and postaxial polydactyly are all examples of non-syndromic polydactyly (ulnar). An autosomal dominant disorder with varying penetrance that is mostly passed down via limb development patterning abnormalities. METHOD: A comprehensive search of MEDLINE/PubMed and other databases was followed by an evaluation of the relevant papers, with a particular focus on those published between 2000 and 2022. RESULTS: Of 747 published article related to Polydactyly from MEDLINE/PubMed search, 43 were from the last 10 years and were the focus of this review. CONCLUSION: Polydactyly is one of the most frequent congenital hand malformations. PAP is more common than PPD, whereas central polydactyly is very uncommon.

Blood utilization and quality indicators at a university hospital in the Eastern Province of Saudi Arabia.

BACKGROUND: Blood transfusion is a common, essential procedure when treating many different medical and surgical conditions. Efficient utilization of blood bank facilities by frequent auditing is crucial; however, few studies have examined blood utilization in Saudi Arabia. We aimed to review the blood ordering patterns and transfusion practices, and blood bank audit effectiveness at a single center in Saudi Arabia and compare our results with those of a similar study performed in the same center 20 years ago. MATERIALS AND METHODS: This study was a retrospective descriptive chart review of all healthy blood donors and recipients from January 1, 2016, to December 31, 2020. We evaluated the crossmatching-to-transfusion ratio (C/T) as an indicator of blood bank utilization and compared the findings with those of the previous study. We also evaluated changes in blood bank utilization during the coronavirus disease 2019 pandemic. RESULTS: Findings from 27,414 donors (men, 94.9%; mean age, 32.2 + 9.6 years) showed a 71% increase in blood donations compared to that of 2000. The donations gradually increased over the years, peaking just before COVID-19 pandemic started in March 2020. For 3,836 patients, 13,324 units of blood were crossmatched (average, 3.47 crossmatch/patient), with 23% of the crossmatch requests from surgical departments. The average C/T ratio, transfusion index, and transfusion probability (T%) were 1.37, 2.55, and 73.2%, respectively. The C/T ratio decreased by 54% between 2000 and 2020. During the pandemic, crossmatching decreased by 26% between 2019 and 2020, but with comparable C/T ratio in 2019 (1.45) and 2020 (1.39). CONCLUSION: Our hospital blood bank utilization improved over the past 20 years, showing increased donations, reduced C/T ratio, and increased T%. This improvement emphasizes the importance of blood donation campaigns, blood bank auditing, restrictive transfusion guidelines, and physician education.

Clinical profile, risk factors and outcomes of ric COVID-19: a retrospective cohort multicentre study in Saudi Arabia.

OBJECTIVE: To describe the risk factors, clinical profile and outcomes of COVID-19 in the paediatric population. DESIGN: Multicentre, retrospective observational study. SETTING: Four tertiary hospitals in Saudi Arabia. PATIENTS: We recruited 390 paediatric patients aged 0-18 years who presented from March to December 2020 and tested positive for COVID-19 on PCR. MAIN OUTCOME MEASURES: We retrospectively analysed medical records for sociodemographics, health indicators, clinical presentations, laboratory findings, clinical complications, and outcomes. RESULTS: The mean participant age was 5.66±4.90 years, and the mean hospital stay was 2.17±3.48 days. Forty patients, mostly school-aged children (16, 40.00%; p=0.005) and children with comorbidities (25, 62.50%; p<0.001), received more than just supportive care. Complications were seen in 15 (3.9%) patients, bacterial infection being the most common (6, 40.00%). Patients presented with dyspnoea (OR 6.89; 95% CI 2.89 to 20.72), abnormal chest radiographs (OR 6.11; 95% CI 1.26 to 29.38), lethargy (OR 9.04; 95% CI 2.91 to 28.06) and elevated ferritin (OR 14.21; 95% CI 4.18 to 48.37) and D-dimer (OR 48.40; 95% CI 14.32 to 163.62), with higher odds of developing complications. The odds of paediatric intensive care unit (ICU) admission were higher for patients with dyspnoea (adjusted OR 4.66; 95% CI 1.24 to 17.50) and elevated white blood cell count (adjusted OR 3.54; 95% CI 1.02 to 12.30). CONCLUSIONS: COVID-19 complications were limited among our patients. However, dyspnoea, abnormal chest radiographs, lethargy and elevated ferritin and D-dimer were associated with an increased risk of complications. Dyspnoea, leucocytosis, comorbidities and abnormal chest radiographs at presentation increased the risk of ICU admission.

Novel Compound Heterozygous Variants of the ABCC8 Gene Warrant Identification of Pancreatic Histology in Infant with Diazoxide-unresponsive Congenital Hyperinsulinism.

Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion, resulting in severe hypoglycemia. Mutations in the ABCC8 and KCNJ11 genes encoding KATP channels in beta cells of the pancreas are common among patients with CHI. Autosomal recessive CHI with diffuse involvement is the most common type of CHI among Saudi patients. It is relatively common for patients with autosomal recessive CHI to be medically unresponsive and undergo pancreatectomy. In this case report, we describe novel compound heterozygous variants in the ABCC8 gene in a Saudi infant that caused diazoxide-unresponsive CHI. The variants included a monoallelic paternally inherited variant that has been previously reported to cause a focal form of CHI and a maternally inherited variant of unknown significance (VUS). The severity of CHI in this patient was mild over the one-year follow-up period, with a near-optimal glycemic response on a low dose of octreotide. We suspected an atypical subtype of histological involvement in the patient. In this report, we highlight the phenotypic spectrum of novel compound heterozygous variants in a patient with CHI and consider that the report can help establish the pathogenicity of the VUS.