G2019S Mutation of Leucine-Rich Repeat Kinase 2 Is a Cause of Lewy Body Dementia in Patients With North African Ancestors.

Background: Mutations in the LRRK2 gene are the most common genetic cause of Parkinson disease but are believed to play no significant role in Lewy body disease (LBD).

Objectives: As the frequency of G2019S LRRK2 mutation is extremely high in North African patients with Parkinson disease, we postulate that the high prevalence of LBD in North Africa might be due to the same mutation because LBD and Parkinson disease share many clinical, pathological, and genetic features.

Methods: We screened patients with LBD or prodromal LBD for the G2019S mutation of LRRK2.

POT1 tumour predisposition: a broader spectrum of associated malignancies and proposal for additional screening program.

Protection of Telomeres Protein 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex, regulating telomere length. Some POT1 gene pathogenic variants (PV) lead to telomere elongation, genomic instability and higher risk of cancer. POT1 tumour predisposition syndrome (POT1-TPD) has autosomal dominant inheritance and unknown penetrance.

A milder form of NSRP1-associated neurodevelopmental disorder, caused by a missense variant in the nuclear localization signal.

Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a splice factor found in nuclear speckles, which are small membrane-free organelles implicated in epigenetic regulation, chromatin organization, DNA repair, and RNA modification. Bi-allelic loss-of-function variants in NSRP1 have recently been identified in patients suffering from a severe neurodevelopmental disorder, presenting with neurodevelopmental delay, epilepsy, microcephaly, hypotonia, and spastic cerebral palsy. Described patients acquired neither independent walking nor speech and often showed anomalies on cerebral MRI.

STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive.

Prioritization of oligogenic variant combinations in whole exomes.

Motivation: Whole exome sequencing (WES) has emerged as a powerful tool for genetic research, enabling the collection of a tremendous amount of data about human genetic variation. However, properly identifying which variants are causative of a genetic disease remains an important challenge, often due to the number of variants that need to be screened. Expanding the screening to combinations of variants in two or more genes, as would be required under the oligogenic inheritance model, simply blows this problem out of proportion.

A novel homozygous variant in gene associated with pontocerebellar hypoplasia type 1E: a case report.

Neonatal encephalopathy (NE) is a complex clinical condition with diverse etiologies. Hypoxic-ischemic encephalopathy (HIE) is a major contributor to NE cases. However, distinguishing NE subtypes, such as pontocerebellar hypoplasia type 1E (PCH1E), from HIE can be challenging due to overlapping clinical features.

Comprehensive evaluation of the implementation of episignatures for diagnosis of neurodevelopmental disorders (NDDs).

Episignatures are popular tools for the diagnosis of rare neurodevelopmental disorders. They are commonly based on a set of differentially methylated CpGs used in combination with a support vector machine model. DNA methylation (DNAm) data often include missing values due to changes in data generation technology and batch effects.

An exome-wide study of renal operational tolerance.

Background: Renal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients.

Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases.

Although standards and guidelines for the interpretation of variants identified in genes that cause Mendelian disorders have been developed, this is not the case for more complex genetic models including variant combinations in multiple genes. During a large curation process conducted on 318 research articles presenting oligogenic variant combinations, we encountered several recurring issues concerning their proper reporting and pathogenicity assessment. These mainly concern the absence of strong evidence that refutes a monogenic model and the lack of a proper genetic and functional assessment of the joint effect of the involved variants.

Identification of differentially methylated regions in rare diseases from a single-patient perspective.

Background: DNA methylation (5-mC) is being widely recognized as an alternative in the detection of sequence variants in the diagnosis of some rare neurodevelopmental and imprinting disorders. Identification of alterations in DNA methylation plays an important role in the diagnosis and understanding of the etiology of those disorders. Canonical pipelines for the detection of differentially methylated regions (DMRs) usually rely on inter-group (e.

Clinical and molecular diagnosis of genodermatoses: Review and perspectives.

Genodermatoses are a complex and heterogeneous group of genetic skin disorders characterized by variable expression and clinical and genetic heterogeneity, rendering their diagnosis challenging. DNA-based techniques, like whole-exome sequencing, can establish a diagnosis in 50% of cases. RNA-sequencing is emerging as an attractive tool that can obtain information regarding gene expression while integrating functional genomic data with regard to the interpretation of variants.

Comparative study of keratinocyte primary culture methods from paediatric skin biopsies for RNA-sequencing.

Background: Keratinocyte culture is a standard method used to study gene expression, cell differentiation and proliferation. Numerous protocols exist, however their application is frequently unsuitable for small specimens, such as 4-mm punch skin biopsies.

Aims: This study compared 3 different methods of keratinocyte culture from paediatric skin biopsies to evaluate which one ensures adequate cell growth for RNA extraction and sequencing.

Early-onset and severe pulmonary arterial hypertension due to a novel compound heterozygous association of rare mutations: A case report and review of existing data.

Very rare cases of pulmonary arterial hypertension (PAH) have been linked to homozygous or compound heterozygous von Hippel-Lindau () tumor suppressor gene mutations, while heterozygous mutations lead to VHL tumor syndrome. Although those entities are defined, the genotype-phenotype correlation is incompletely understood, and patient management recommendations are lacking. Here, we describe a case of severe early-onset PAH due to a so-far unreported compound heterozygous association of mutations and review the existing data.

Scaling up oligogenic diseases research with OLIDA: the Oligogenic Diseases Database.

Unlabelled: Improving the understanding of the oligogenic nature of diseases requires access to high-quality, well-curated Findable, Accessible, Interoperable, Reusable (FAIR) data. Although first steps were taken with the development of the Digenic Diseases Database, leading to novel computational advancements to assist the field, these were also linked with a number of limitations, for instance, the ad hoc curation protocol and the inclusion of only digenic cases. The OLIgogenic diseases DAtabase (OLIDA) presents a novel, transparent and rigorous curation protocol, introducing a confidence scoring mechanism for the published oligogenic literature.

Evaluation of neurodevelopmental symptoms in 10 cases of neonatal ichthyosis and sclerosing cholangitis syndrome.

Neonatal ichthyosis and sclerosing cholangitis (NISCH) syndrome is an extremely rare entity with only 19 patients described in the literature. We report an extended family with the disorder and investigate the association of neurodevelopmental symptoms. Patients with CLDN1 mutations, and specifically « the Moroccan» c.

Rarity of fetal cells in exocervical samples for noninvasive prenatal diagnosis.

Objectives: The possibility to isolate fetal cells from pregnant women cervical samples has been discussed for five decades but is not currently applied in clinical practice. This study aimed at offering prenatal genetic diagnosis from fetal cells obtained through noninvasive exocervical sampling and immuno-sorted based on expression of HLA-G.

Methods: We first developed and validated robust protocols for cell detection and isolation on control cell lines expressing (JEG-3) or not (JAR) the HLA-G antigen, a specific marker for extravillous trophoblasts.

Case Report: Homozygous Pathogenic Variant P209L in the Gene: A Rare Cause of End Stage Renal Disease and Biliary Cirrhosis Requiring Combined Liver-Kidney Transplantation. A Case Report and Literature Review.

Ciliopathies are rare diseases causing renal and extrarenal manifestations. Here, we report the case of a ciliopathy induced by a homozygous pathogenic variant in the gene. A 47-year-old patient started hemodialysis for chronic kidney disease (CKD) of unknown origin.

Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts.

Purpose: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy.

Methods: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy.

Acquired Zinc Deficiency Mimicking Acrodermatitis Enteropathica in a Breast-Fed Premature Infant.

We present a case of a transient acquired zinc deficiency in a breast-fed, 4-month-old-male prematurely born infant, with acrodermatitis enteropathica-like symptoms such as crusted, eroded, erythemato-squamous eruption in periorificial and acral patterns. The laboratory investigations showed low zinc levels in the infant's and the mother's serum and in the mother's milk; genetic analysis did not show any mutation in the gene, involved in acrodermatitis enteropathica. Acquired zinc deficiency is often found in premature infants because of their increased requirement, the low serum and milk zinc levels in breastfeeding women being also an important risk factor, as in this case.

Spontaneous resolution of nonimmune hydrops fetalis in a fetus with gene mutation and gene variants.

In cases of fetal hydrops, searching for an etiology is essential to evaluate the fetal prognosis and propose the most appropriate management.

Performance and Diagnostic Value of Genome-Wide Noninvasive Prenatal Testing in Multiple Gestations.

Objective: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies.

Methods: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography.