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Ciliopathies represent a major category of rare multisystem disease. Arriving at a specific diagnosis for a given patient is challenged by the significant genetic and clinical heterogeneity of these conditions. We report the outcome of the diagnostic odyssey of a child with obesity, renal, and retinal disease. Genome sequencing identified biallelic splice site variants in sodium channel and clathrin linker 1 (SCLT1), an emerging ciliopathy gene. We review the literature on all patients reported with biallelic SCLT1 variants highlighting a frequent clinical presentation that overlaps Bardet–Biedl and Senior–Loken syndromes. We also discuss current concepts in syndrome designation in light of these data. [ABSTRACT FROM AUTHOR]

Tamas Fulop,1 Shreyansh Tripathi,2,3 Serafim Rodrigues,3,4 Mathieu Desroches,5,6 Ton Bunt,7 Arnold Eiser,8 Francois Bernier,9 Pascale B Beauregard,10 Annelise E Barron,11 Abdelouahed Khalil,1 Adam Plotka,12 Katsuiku Hirokawa,13 Anis Larbi,14 Christian Bocti,15 Benoit Laurent,16 Eric H Frost,17 Jacek M Witkowski12 1Research Center on Aging, Geriatric Division, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 2Cluster Innovation Centre, North Campus, University of Delhi, Delhi, 110007, India; 3Ikerbasque, The Basque Foundation for Science, Bilbao, Spain; 4Mathematical Computational and Experimental Neuroscience (MCEN), BCAM - The Basque Center for Applied Mathematics, Bilbao, Spain; 5MathNeuro Team, Inria Sophia Antipolis Méditerranée, Sophia Antipolis, France; 6Department of Mathematics, Université Côte d’Azur, Nice, France; 7Izumi Biosciences, Inc., Lexington, MA, USA; 8Leonard Davis Institute, University of Pennsylvania, Drexel University College of Medicine, Philadelphia, PA, USA; 9Morinaga Milk Industry Co., Ltd, Next Generation Science Institute, Kanagawa, Japan; 10Department of Biology, Faculty of Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 11Department of Bioengineering, Stanford School of Medicine, Stanford, CA, USA; 12Department of Pathophysiology, Medical University of Gdansk, Gdansk, Poland; 13Institute of Health and Life Science, Tokyo Med. Dent. University, Tokyo and Nito-Memory Nakanosogo Hospital, Department of Pathology, Tokyo, Japan; 14Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Biopolis, Singapore, Singapore; 15Research Center on Aging, Department of Medicine, Division of Neurology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 16Research Center on Aging, Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; 17Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, CanadaCorrespondence: Tamas FulopResearch Center on Aging, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, Quebec, J1H 5N4, CanadaTel +1 819 780 2220Fax +1 819 829 7141Email tamas.fulop@usherbrooke.caSerafim RodriguesIkerbasque Prof. Dr., Ikerbasque, The Basque Foundation for Science Bilbao, Spain and BCAM - The Basque Center for Applied Mathematics, Mathematical, Computational and Experimental (MCEN) Research Group, Alameda de Mazarredo 14, Bilbao, Bizkaia, Basque-Country, 48009, SpainTel +34 946 567 842Email srodrigues@bcamath.orgAbstract: Alzheimer’s disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.Keywords: Alzheimer’s disease, mild cognitive impairment, neuroinflammation, antimicrobial immunity, brain, treatment

Introduction: Early identification of autism spectrum disorders (ASD) is important, since earlier exposure to behavioural intervention programs may result in better outcomes for the child. Moreover, it allows families timely access to other treatments and supports. Methods: Using generalized linear modeling, we examined the association between child and family characteristics and the age at which 2180 children were diagnosed with ASD between 1997 and 2005 in six Canadian regions. Results: A diagnosis of pervasive developmental disorder-not otherwise specified (PDD-NOS) or Asperger syndrome, rural residence, diagnosis in more recent years, and foreign birthplace were associated with a later age at diagnosis. Children who are visible minorities or who have siblings with ASD were more likely to be diagnosed earlier. Collectively, these factors explained little of the variation in age at diagnosis, however. Conclusion: While it is encouraging that ethnocultural identity, neighbourhood income, urban or rural residence, and sex of the child were not major contributors to disparities in the age when children were identified with ASD, more work is needed to determine what does account for the differences observed. Regional variations in the impact of several factors suggest that aggregating data may not be an optimal strategy if the findings are meant to inform policy and clinical practice at the local level. [ABSTRACT FROM AUTHOR]

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community., (© 2023. The Author(s).)

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Background: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown., Aims: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada., Materials & Methods: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives., Results: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family., Conclusion: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mutations in GLE1 cause two recessive subtypes of arthrogryposis multiplex congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period. GLE1 related AMC has been almost exclusively reported in the Finnish population and is caused by a relatively common pathogenic splicing mutation in that population. Here, we report two non-Finnish brothers with novel compound heterozygous splicing mutations in GLE1, one of whom has survived to 12 years of age. We also demonstrate low levels of residual wild type transcript in fibroblasts from the surviving brother, suggesting that this residual wild-type transcript may contribute to the relatively longer-term survival in this family. We provide a detailed clinical report on the surviving patient, providing the first insight into the natural history of this rare neuromuscular disease. We also suggest that lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn disease (LAAHD), the two AMC subtypes related to GLE1, do not have sufficient clinical or molecular differentiation to be considered allelic disorders. Rather, GLE1 mutations cause a variable spectrum of AMC severity including a non-lethal variant described herein., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The purpose of the study was to delineate the anomalies and the natural life history of persons with the Bowen-Conradi syndrome [Bowen and Conradi 1976: Birth Defects: Orig Artic Ser XII(6):101-108]. We ascertained 39 cases and personally examined almost all. For those who were not seen, their clinical record were scrutinized. Pedigree analysis of all 39 was done and kinship coefficients computed. The birth prevalence was estimated to be 1/355 live births., (Copyright 2003 Wiley-Liss, Inc.)

Objectives: Our objectives were to confirm the reported association between early amniocentesis and congenital foot anomalies as well as to report, for the first time, on the outcome of amniocenteses performed during the 13th and 14th weeks of gestation., Methods: We conducted a triple cohort retrospective study of 4457 amniocenteses. Cohort definitions: early amniocentesis (EA), 11 weeks and 0/7 days to 12 weeks to 6/7 days; early midtrimester amniocentesis (EMA), 13 weeks and 0/7 days to 14 weeks and 6/7 days; and midtrimester amniocentesis (MA), 15 weeks and 0/7 days to 19 weeks and 6/7 days. Outcome measures were obtained by searching the Alberta Congenital Anomalies Surveillance System (ACASS) database for children born with foot anomalies represented by International Classification of Diseases version 9 (ICD-9) codes 754.5, 754.6 and 754.7., Results: Incidences of congenital foot anomalies were: EA 11/980 (1.1%), EMA 11/2515 (0.4%), and MA 1/962 (0.1%). There is a significant difference between the EA and EMA cohorts (p=0.019) and between the EA and MA cohorts (p=0.003); however, these data suggest there is no difference between EMA and MA cohorts (p=0.11)., Conclusions: Our incidence of congenital foot anomalies of 1.1% for women who underwent EA is similar to previously reported data, which further validates this association; however, our data also suggest that the foot anomaly risk may be limited to amniocenteses performed before the 13th week of gestation., (Copyright 2001 John Wiley & Sons, Ltd.)

We have determined the molecular basis for Usher syndrome type 1F (USH1F) in two families segregating for this type of syndromic deafness. By fluorescence in situ hybridization, we placed the human homolog of the mouse protocadherin Pcdh15 in the linkage interval defined by the USH1F locus. We determined the genomic structure of this novel protocadherin, and found a single-base deletion in exon 10 in one USH1F family and a nonsense mutation in exon 2 in the second. Consistent with the phenotypes observed in these families, we demonstrated expression of PCDH15 in the retina and cochlea by RT-PCR and immunohistochemistry. This report shows that protocadherins are essential for maintenance of normal retinal and cochlear function.

A single-blind study of dystrophin staining in skeletal muscle was performed in 13 biopsies from carriers of Duchenne Muscular Dystrophy (DMD) and controls. The results indicate that immunohistochemical analysis of dystrophin staining is a valuable diagnostic test for DMD carriers when DNA for testing is unavailable from critical family members or is uninformative, when creatine kinase (CK) values are conflicting or when CK values must be used in isolation.