Paul Renbaum

A conditional Vrk1 cholinergic knockout mouse recapitulates severe human motor neuron disease

Shlomit Golan-Malul, Itai Greenbaum, Avital Schauder, Stephanie Oren et autres

Mutations in the VRK1 (Vaccinia-related kinase 1) gene have been implicated in neurodegenerative disease, primarily affecting motor neurons (MNs) and brain development. However, VRK1’s role in MN function and underlying disease mechanisms remain poorly understood. In this study, we investigated VRK1’s role …

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Reversible mitochondrial iron toxicity in Wolfram syndrome type 2 monogenic diabetes

Amitay Cohen, Ola Karmi, Ulla Najwa Abdulhag, Tehila Klopstock et autres

CONTEXT: Wolfram syndrome type 2 (WS2) is a rare monogenic diabetes syndrome caused by CISD2 mutations. Its cellular pathophysiology remains poorly understood, and no targeted therapies exist. OBJECTIVE: To characterize the clinical phenotype and cellular pathophysiology of the largest WS2 cohort to …

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Biallelic SUPT4H1 variants cause a multisystem neurodevelopmental disorder associated with disrupted transcription

Christina Canavati, Mari Oppebøen, Radha Verma, Doriana Misceo et autres

PURPOSE: We aimed to define the clinical and genetic basis of an autosomal recessive neurodevelopmental disorder identified in 3 unrelated families with an overlapping multisystem phenotype. METHODS: Exome or genome sequencing was performed in 6 affected individuals from 3 families, revealing biallelic …

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[Resolving Genomic Mysteries with Long-read Sequencing].

Omer Murik, David A. Zeevi, Tzvia Mann, Rachel Beeri et autres

INTRODUCTION: Short-read next-generation sequencing (srNGS, 50-300 bp) has become the predominant first-line test for diagnosing patients with rare genetic conditions. However, this technology has inherent limitations, including reduced diagnostic yield for structural variants (SVs) and variants located in repetitive or highly homologous …

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Alleviating Mitochondrial Stress Improves Symptoms in Wolfram Syndrome Type 2

Amitay Cohen, Ola Karmi, Ulla Najwa Abdulhag, Tehila Klopstock et autres

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P-567 Cycle outcomes using Haploseek combining PGT-M and PGT-A compared to PGT-M only in patients tested for monogenic diseases

Michal Youngster, Nechama Sharon, Irit Granot, Alon Kedem et autres

Abstract Study question Is there a difference in cycle outcomes when embryos are tested solely for monogenic diseases (PGT-M) or a combination of PGT-M and chromosomal abnormalities (PGT-A)? Summary answer The Haploseek combining PGT-M & PGT-A resulted in higher pregnancy rates per …

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A Novel Homozygous BMP15 Mutation Causes Ovarian Dysgenesis and Primary Amenorrhea

Amitay Cohen, Raffaella Rossetti, Natan Florsheim, Abraham O. Samson et autres

Context: Despite a growing number of studies, the genetic etiology in many cases of ovarian dysgenesis is incompletely understood. Objectives: This work aimed to study the genetic etiology causing absence of spontaneous pubertal development, hypergonadotropic hypogonadism, and primary amenorrhea in 2 sisters. …

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Discovering predisposing genes for hereditary breast cancer using deep learning

Gal Passi, Sari Lieberman, Fouad Zahdeh, Omer Murik et autres

Breast cancer (BC) is the most common malignancy affecting Western women today. It is estimated that as many as 10% of BC cases can be attributed to germline variants. However, the genetic basis of the majority of familial BC cases has yet …

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Using multi-scale genomics to associate poorly annotated genes with rare diseases

Christina Canavati, Dana Sherill-Rofe, Lara Kamal, Idit Bloch et autres

BACKGROUND: Next-generation sequencing (NGS) has significantly transformed the landscape of identifying disease-causing genes associated with genetic disorders. However, a substantial portion of sequenced patients remains undiagnosed. This may be attributed not only to the challenges posed by harder-to-detect variants, such as non-coding …

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Additional file 1 of Using multi-scale genomics to associate poorly annotated genes with rare diseases

Christina Canavati, Dana Sherill-Rofe, Lara Kamal, Idit Bloch et autres

Additional file 1: Table S1. Clinical and Genetic Characteristics of the 109-Patient Exome Dataset. Table S2. ClinVar-Simulated Genetic Variants and Associated Phenotypes. Table S3. Newly added disease-gene entries in the Human Phenotype Ontology (HPO) database.

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SHaploseek is a sequencing-only, high-resolution method for comprehensive preimplantation genetic testing

Daniel Backenroth, Gheona Altarescu, Fouad Zahdeh, Tzvia Mann et autres

Recent advances in genomic technologies expand the scope and efficiency of preimplantation genetic testing (PGT). We previously developed Haploseek, a clinically-validated, variant-agnostic comprehensive PGT solution. Haploseek is based on microarray genotyping of the embryo's parents and relatives, combined with low-pass sequencing of …

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Loss of function of FIGNL1, a DNA damage response gene, causes human ovarian dysgenesis

Natan Florsheim, Larisa Naugolni, Fouad Zahdeh, Orit Lobel et autres

Ovarian dysgenesis (OD), an XX disorder of sex development, presents with primary amenorrhea, hypergonadotrophic hypogonadism, and infertility. In an Ashkenazi Jewish patient with OD, whole exome sequencing identified compound heterozygous frameshifts in FIGNL1, a DNA damage response (DDR) gene: c.189del and c.1519_1523del. …

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