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.

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.

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.

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.

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.

Identification of RPL5 gene variants and the risk of hepatic vein thrombosis in Saudi patients.

OBJECTIVES: To identify ribosome protein L5 gene variants and the risk of hepatic vein thrombosis in Saudi patients. METHODS: A case-control study was conducted during the period of May 2018 to September 2019. Sixty-five patient cases of hepatic vein thrombosis (HVT) were chosen, and 50 healthy individuals of the same ages and both gender were set as a control group. The genotype of the gene RPL5 was determined by PCR please provide abbreviation in full and capillary electrophoresis. Sanger sequencing for genetically screened variants was applied for the RPL5 gene. RESULTS: Alleles A at variant rs182018447 and T allele at variant rs559377519 were strongly corelated (p=0.009 and p=0.037, respectively) with the risk of HVT. The genotype frequencies of the RPL5 gene, the A/A genotypes at rs182018447 and T/T at rs559377519 were associated with HVT (p=0.000 and p=0.004; respectively) and an increase in risk for HVT among these patients. Please rephrase the highlighted text without using the word respectively. CONCLUSION: Our findings indicate that the 5 genetic novel variants examined in the RPL5 gene were associated with a risk of HVT in all our Saudi cases. Additionally, the A/A at rs182018447 and T/T at rs559377519 genotypes were substantially susceptible to HVT in all these patients.

Malignant Infantile Osteopetrosis: A Case Report.

Osteopetrosis is a rare genetic disease of bone resorption. It includes a variety of hereditary skeletal disorders that have the main radiographic feature of increased bone density and thickness due to differentiation or functional defects in osteoclast. The clinical presentation varies widely based on the type of osteopetrosis and ranges in severity from asymptomatic to a fatal course. Our case is of the infantile malignant osteopetrosis (IMOP) form. It is inherited as an autosomal recessive pattern that generally starts in intrauterine life and manifests at birth or early childhood. It is the most severe form and has an incidence of 1 in 250,000 births. The patient presented at the age of two months with a history of recurrent fever, recurrent pneumonia, developmental delay, and infantile spasms. Upon examination, she was found to have hepatosplenomegaly, axial hypotonia, limb spasticity, and visual impairment. Genetic testing revealed a homozygous variant of OSTM1 gene, which is a known Saudi mutation of autosomal recessive osteopetrosis (ARO). IMOP should be considered as a rare differential of hepatosplenomegaly. Early diagnosis by clinical picture, imaging, and genetic testing is important to direct the appropriate management in order to prevent disease progression before the irreversible neurological sequelae occur. Patients should be managed by a comprehensive approach, and currently, hematopoietic stem cell transplantation (HSCT) provides a better outcome for IMOP patients.

Use of a Mortality Prediction Model in Children on Mechanical Ventilation: A 5-Year Experience in a Tertiary University Hospital.

PURPOSE: Currently, several scoring systems for predicting mortality in severely ill children who require treatment in a pediatric intensive care unit (PICU) have been established. However, despite providing high-quality care, children might develop complications that can cause rapid deterioration in health status and can lead to death. Hence, this study aimed to establish a simple early predictive mortality (SEPM) model with high specificity in identifying severely ill children who would possibly benefit from extensive mechanical ventilation during PICU admission. PATIENTS AND METHODS: This is a retrospective longitudinal study that included pediatric patients aged older than two weeks who were on mechanical ventilation and were admitted to the PICU of King Fahd Hospital of the University from January 2015 to December 2019. RESULTS: In total, 400 pediatric patients were included in this study. The mortality rate of children on mechanical ventilation was 28.90%, and most deaths were associated with respiratory (n = 124 [31%]), cardiovascular (n = 76 [19%]), and neurological (n = 68 [17%]) causes. The SEPM model was reported to be effective in predicting mortality, with an accuracy, specificity, and sensitivity of 92.5%, 97.31%, and 66.15%, respectively. Moreover, the accuracy, specificity, and sensitivity of the Pediatric Risk of Mortality (PRISM) III score in predicting mortality was 95.25%, 98.51%, and 78.46%, respectively. CONCLUSION: The SEPM model had a high specificity for mortality prediction. In this model, only six clinical predictors were used, which might be easily obtained in the early period of PICU admission. The ability of the SEPM model and the PRISM III score in predicting mortality in severely ill children was comparable. However, the accuracy of the newly established model in other settings should be validated, and a prospective longitudinal study that considers the effect of the treatment on the model's predictive ability must be conducted.

Aortic calcification in Gaucher disease: a case report.

Gaucher disease is the most common sphingolipid storage disease and is present in all ethnic groups. Its symptoms span all systems including the cardiovascular system. The health care provider should be vigilant regarding this potentially fatal complication. Gaucher disease type IIIC has been linked to causing oculomotor apraxia and cardiac calcification. We report a Saudi girl who developed valvular and aortic calcification in late childhood and died as a result of her cardiovascular complications. This report further strengthens the association and reminds the clinicians that patients with D409H mutation need echocardiographic evaluation annually.

The phenotype, genotype, and outcome of infantile-onset Pompe disease in 18 Saudi patients.

Infantile-Onset Pompe Disease (IOPD) is an autosomal recessive disorder of glycogen metabolism resulting from deficiency of the lysosomal hydrolase acid α-glucosidase encoded by GAA gene. Affected infants present before the age of 12 months with hypotonia, muscle weakness, and hypertrophic cardiomyopathy. Enzyme replacement therapy (ERT) has been shown to improve survival, cardiac mass, and motor skills. In this work, we aim to illustrate the genotypes of IOPD and the outcome of ERT in our population. The medical records of infants with confirmed diagnosis of IOPD who received ERT were reviewed. Eighteen infants (7 males, 11 females) were included in the study. The median age at presentation was 2 months and the median age at the start of ERT was 4.5 months. Fifteen (83.3%) infants died with a median age at death of 12 months. The 3 alive infants (whose current ages are 6½â€¯years, 6 years, and 10 years), who were initiated on ERT at the age of 3 weeks, 5 months, and 8 months respectively, has had variable response with requirement of assisted ventilation in one child and tracheostomy in another child. All infants were homozygous for GAA mutations except one infant who was compound heterozygous. All infants (n = 8) with truncating mutations died. Our work provides insight into the correlation of genotypes and outcome of ERT in IOPD in Saudi Arabia. Our data suggest that early detection of cases, through newborn screening, and immunomodulation before the initiation of ERT may improve the outcome of ERT in Saudi infants with IOPD.

Depression in adult patients with biotin responsive basal ganglia disease.

Biotin responsive basal ganglia disease (BBGD), is a potentially treatable inherited metabolic disorder which clinically presents as sub-acute encephalopathy in children. Early diagnosis and treatment of this disorder results in good clinical recovery in childhood. However, there is no report in the literature on the long term outcome of these treated patients in adult life. We report two patients with BBGD who were metabolically stable on treatment and developed depression later in life. These cases highlight the association of depression with basal ganglia disorders and demonstrate that depression is the potential long term complication of BBGD.

Clinical description of human bocavirus viremia in children with LRTI, Eastern Province, Saudi Arabia.

Human bocavirus (HBoV) is a major etiology of lower respiratory tract infection (LRTI) in young children. We tested 149 patients admitted to King Fahd Hospital of the University with diagnosis of LRTI. Viremia caused by the different studied viruses was detected in 31.5% of the total cases by Real-time Polymerase chain reaction. We report five patients who were positive for HBoV in serum samples. Clinical presentation ranged from mild to severe disease as one of them required admission to intensive care unit. Wheezing was a striking feature in most of our patients, but fever was not a consistent finding.

Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families.

BACKGROUND: Identifying genetic variants that lead to discernible phenotypes is the core of Mendelian genetics. An approach that considers embryonic lethality as a bona fide Mendelian phenotype has the potential to reveal novel genetic causes, which will further our understanding of early human development at a molecular level. Consanguineous families in which embryonic lethality segregates as a recessive Mendelian phenotype offer a unique opportunity for high throughput novel gene discovery as has been established for other recessive postnatal phenotypes. RESULTS: We have studied 24 eligible families using autozygosity mapping and whole-exome sequencing. In addition to revealing mutations in genes previously linked to embryonic lethality in severe cases, our approach revealed seven novel candidate genes (THSD1, PIGC, UBN1, MYOM1, DNAH14, GALNT14, and FZD6). A founder mutation in one of these genes, THSD1, which has been linked to vascular permeability, accounted for embryonic lethality in three of the study families. Unlike the other six candidate genes, we were able to identify a second mutation in THSD1 in a family with a less severe phenotype consisting of hydrops fetalis and persistent postnatal edema, which provides further support for the proposed link between this gene and embryonic lethality. CONCLUSIONS: Our study represents an important step towards the systematic analysis of "embryonic lethal genes" in humans.