Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans.

Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. In two Arab consanguineous families, we mapped a ciliopathy phenotype that most closely matches Joubert syndrome (hypotonia, developmental delay, typical facies, oculomotor apraxia, polydactyly, and subtle posterior fossa abnormalities) to a single locus in which a founder homozygous truncating variant in FAM149B1 was identified by exome sequencing. We subsequently identified a third Arab consanguineous multiplex family in which the phenotype of Joubert syndrome/oral-facial-digital syndrome (OFD VI) was found to co-segregate with the same founder variant in FAM149B1. Independently, autozygosity mapping and exome sequencing in a consanguineous Turkish family with Joubert syndrome highlighted a different homozygous truncating variant in the same gene. FAM149B1 encodes a protein of unknown function. Mutant fibroblasts were found to have normal ciliogenesis potential. However, distinct cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling. We conclude that FAM149B1 is required for normal ciliary biology and that its deficiency results in a range of ciliopathy phenotypes in humans along the spectrum of Joubert syndrome.

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects.

Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.

The Role of Genetic Testing in Pediatric Renal Diseases: Diagnostic, Prognostic, and Social Implications.

Pediatric renal diseases vary widely and are linked to high morbidity and mortality; hence, early diagnosis is vital. Presently, genetic testing is being incorporated into the standard of care for children and their families with kidney disease, primarily as a diagnostic tool. In the present review, we aim to collect all potential evidence from relevant studies that reported the role of genetic testing in pediatric renal disease diagnostic, prognostic, and social implications. We have conducted both electronic and manual searches within PubMed, the Cochrane Library, Web of Science, and Scopus to find relevant studies. Studies from the years 2013-2023 were included. Case reports with limited sample sizes and no descriptive statistics, along with review papers and meta-analyses, were excluded from this review. Quality assessment for all included studies was performed. The pooled diagnostic yields were calculated using the common effect and random effect models utilizing the R program (R Foundation for Statistical Computing, Vienna, Austria). The pooled result for the diagnostic yield as per the common effect model is a pooled proportion of 0.42 (42%) 95% confidence interval (CI): [0.39,0.44], while with the random effects model the pooled proportion is 0.43 (43%) 95% CI: [0.31,0.57]. The diagnostic yield for the included studies ranged from 78.10% to 16.8%. The spectrum of kidney diseases included nephrolithiasis/nephrocalcinosis, glomerular diseases, cystic kidney disease, ciliopathies, tubulopathies, chronic kidney disease, and congenital anomalies of the kidneys and urinary tracts (CAKUT), while hematuria and proteinuria were reported by two studies and autosomal recessive and autosomal dominant idiopathic kidney disease was reported by only one study. Genetic testing validates clinical diagnosis and aids in tailoring management strategies; hence, a more precise treatment plan is developed and unnecessary investigations are avoided, which is crucial in the case of children during routine nephrology clinic visits. Genetic counselling is of the utmost importance, so all ethical and social concerns related to genetic testing are addressed in addition to patient satisfaction.

Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.

BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.

Phenotypic and Molecular Spectrum of Aicardi-Goutières Syndrome: A Study of 24 Patients.

BACKGROUND: Aicardi-Goutières syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this study was to review the clinical and molecular diagnostic findings in 24 individuals with Aicardi-Goutières syndrome who presented during childhood in an Arab population. MATERIALS AND METHODS: We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries. All included patients had a molecular diagnosis of Aicardi-Goutières syndrome. RESULTS: Six individuals with Aicardi-Goutières syndrome (25%) had a neonatal presentation, whereas the remaining patients presented during the first year of life. Patients presented with developmental delay (24 cases, 100%); spasticity (24 cases, 100%); speech delay (23 cases, 95.8%); profound intellectual disability (21 cases, 87.5%); truncal hypotonia (21 cases, 87.5%); seizures (eighteen cases, 75%); and epileptic encephalopathy (15 cases, 62.5%). Neuroimaging showed white matter abnormalities (22 cases, 91.7%), cerebral atrophy (75%), and small, multifocal calcifications in the lentiform nuclei and deep cerebral white matter (54.2%). Homozygous mutations were identified in RNASEH2B (54.2%), RNASEH2A (20.8%), RNASEH2C (8.3%), SAMHD1 (8.3%), TREX1 (4.2%), and heterozygous mutations in IFIH1 (4.2%), with c.356A>G (p.Asp119Gly) in RNASEH2B being the most frequent mutation. Three novel mutations c.987delT and c.625 + 1G>A in SAMHD1 gene and c.961G>T in the IFIHI1 gene were identified. CONCLUSIONS: This is the largest molecularly confirmed Aicardi-Goutières syndrome cohort from Arabia. By presenting these clinical and molecular findings, we hope to raise awareness of Aicardi-Goutières syndrome and to demonstrate the importance of specialist referral and molecular diagnosis.

Pulmonary hypertension and vasculopathy in incontinentia pigmenti: a case report.

Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome) is a rare, genetic syndrome inherited as an X-linked dominant trait. It primarily affects female infants and is lethal in the majority of males during fetal life. The clinical findings include skin lesions, developmental defects, and defects of the eyes, teeth, skeletal system, and central nervous system. Cardiovascular complications of this disease in general, and pulmonary hypertension in particular, are extremely rare. This report describes the case of a 3-year-old girl with IP complicated by pulmonary arterial hypertension. Extensive cardiology workup done to the patient indicates underlying vasculopathy. This report sheds light on the relationship between IP and pulmonary hypertension, reviews the previously reported cases, and compares them with the reported case.