Fetal Presentation of MYRF-Related Cardiac Urogenital Syndrome: An Emerging and Challenging Prenatal Diagnosis.

Purpose: MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant.

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

Purpose: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease.

Methods: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5.

The yield of genetic workup for middle-aged and elderly patients with neurological disorders in a real-world setting.

Genetic workup is becoming increasingly common in the clinical assessment of neurological disorders. We evaluated its yield among middle-aged and elderly neurological patients, in a real-world context. This retrospective study included 368 consecutive Israeli patients aged 50 years and older (202 [54.

Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease.

Background: In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa.

Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome.

Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash.

Adult-onset Alexander disease among patients of Jewish Syrian descent.

Alexander disease (AxD) is a rare autosomal dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acid protein (GFAP) gene. The age of symptoms onset ranges from infancy to adulthood, with variable clinical and radiological manifestations. Adult-onset AxD manifests as a chronic and progressive condition, characterized by bulbar, motor, cerebellar, and other clinical signs and symptoms.

Oral and fecal polio vaccine excretion following bOPV vaccination among Israeli infants.

Introduction: Inactivated polio virus (IPV) vaccinations are a mainstay of immunization schedules in developed countries, while oral polio vaccine (OPV) is administered in developing countries and is the main vaccine in outbreaks. Due to circulating wild poliovirus (WPV1) detection in Israel (2013), oral bivalent polio vaccination (bOPV) was administered to IPV primed children and incorporated into the vaccination regimen.

Objectives: We aimed to determine the extent and timeframe of fecal and salivary polio vaccine virus (Sabin strains) shedding following bOPV vaccination among IPV primed children.

Clinical impact of exome sequencing in the setting of a general pediatric ward for hospitalized children with suspected genetic disorders.

Genetic conditions contribute a significant portion of disease etiologies in children admitted to general pediatric wards worldwide. While exome sequencing (ES) has improved clinical diagnosis and management over a variety of pediatric subspecialties, it is not yet routinely used by general pediatric hospitalists. We aim to investigate the impact of exome sequencing in sequencing-naive children suspected of having monogenic disorders while receiving inpatient care.

PPP2R1A neurodevelopmental disorder is associated with congenital heart defects.

Protein phosphatase 2A (PP2A) is a heterotrimeric serine/threonine phosphatase that regulates numerous biological processes. PPP2R1A encodes the scaffolding "Aα" subunit of PP2A. To date, nearly 40 patients have been previously reported with 19 different pathogenic PPP2R1A variants, with phenotypes including intellectual disability, developmental delay, epilepsy, infant agenesis/dysgenesis of the corpus callosum, and dysmorphic features.

Vici syndrome in Israel: Clinical and molecular insights.

Vici Syndrome is a rare, severe, neurodevelopmental/neurodegenerative disorder with multi-systemic manifestations presenting in infancy. It is mainly characterized by global developmental delay, seizures, agenesis of the corpus callosum, hair and skin hypopigmentation, bilateral cataract, and varying degrees of immunodeficiency, among other features. Vici Syndrome is caused by biallelic pathogenic variants in , resulting in impaired autophagy.

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants.

What Can We Learn from the Parents of Children Affected with Mucopolysaccharidosis Type III-A in Israel?

Sanfilippo Syndrome, or mucopolysaccharidosis type III (MPS III), is a group of autosomal-recessive lysosomal storage disorders leading to tissue accumulation of heparan sulfate. MPS III is caused by deficiency in one of 4 enzymes involved in lysosomal degradation of heparan sulfate. Based on the relevant enzyme deficiency, 4 types have been recognized.

Broadening the phenotype of LRRK1 mutations - Features of malignant osteopetrosis and optic nerve atrophy with intrafamilial variable expressivity.

Osteosclerotic metaphyseal dysplasia is a rare disorder which features osteosclerosis involving long bones, vertebrae, ribs, clavicles and the iliac crests. Additional features which have variably been reported include developmental delay, short stature, hypotonia and seizures. The disease is caused by pathogenic variants in the LRRK1 gene, and inherited in an autosomal recessive manner.

A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies.

Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018-2020).

Kidney and urinary tract findings among patients with Kabuki (make-up) syndrome.

Background: Kabuki syndrome (KS) is a genetic disorder caused mainly by de novo pathogenic variants in KMT2D or KDM6A, characterized by recognizable facial features, intellectual disability, and multi-systemic involvement, including short stature, microcephaly, hearing loss, cardiac defects, and additional congenital anomalies. While congenital anomalies of the kidneys and urinary tract (CAKUT) are known manifestations of this disorder, studies focused solely on kidney involvement are scarce, and its prevalence is most likely underestimated. This study aimed to describe the prevalence and nature of CAKUT and other renal manifestations, in a cohort of KS patients followed at a single tertiary center.

Ophthalmic manifestations in Kabuki (make-up) syndrome: A single-center pediatric cohort and systematic review of the literature.

Kabuki syndrome (KS) is a genetic disorder caused by pathogenic variants in KMT2D or KDM6A, and manifesting with multi-systemic involvement, including recognizable facial features, developmental delay and multiple congenital anomalies. Ophthalmological involvement has been described in varying rates in several studies. We aimed to evaluate the prevalence and nature of ophthalmological findings in a cohort of KS patients in Israel.

Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis.

Background: Over half of children with rare genetic diseases remain undiagnosed despite maximal clinical evaluation and DNA-based genetic testing. As part of an Undiagnosed Diseases Program applying transcriptome (RNA) sequencing to identify the causes of these unsolved cases, we studied a child with severe infantile osteopetrosis leading to cranial nerve palsies, bone deformities, and bone marrow failure, for whom whole-genome sequencing was nondiagnostic.

Methods: We performed transcriptome (RNA) sequencing of whole blood followed by analysis of aberrant transcript isoforms and osteoclast functional studies.

Atopic Predilection among Kawasaki Disease Patients: A Cross-Sectional Study of 1,187,757 Teenagers.

Background: Kawasaki disease (KD) is an acute, systemic vasculitis in children, with an etiology that is not completely understood. It is assumed that the development of KD is mediated by an immunologic response. Several reports from East Asia have found a higher prevalence of atopic diseases among patients with KD, but a large-scale study of a non-Asian population regarding this correlation is still lacking.