De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly.

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15).

Dual diagnosis of trisomy 21 and lethal perinatal Gaucher disease as a cause of non-immune hydrops fetalis in a twin pregnancy for a consanguineous couple.

Non-immune hydrops is a prenatal finding which can occur due to an underlying genetic diagnosis such as common chromosomal aneuploidy (Trisomy 21, Turner syndrome etc.). It is extremely rare to have more than one genetic cause of hydrops fetalis in a single pregnancy.

An uninformative NIPT as an early indicator of cri-du-chat due to a chromosomal 5;18 translocation-An atypical presentation of a rare cytogenetic phenomenon.

We present a patient with cri-du-chat syndrome secondary to a rare cytogenetic mechanism. Our patient was the product of a dichorionic diamniotic twin pregnancy initially flagged with soft markers on ultrasound and uninformative single-nucleotide polymorphism (SNP)-based noninvasive prenatal testing (NIPT) for chromosome 18. Subsequent NIPT using proprietary-targeted amplification methodology returned low risk for chromosomal aneuploidies 13, 18, and 21.

Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data.

We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians.

A novel MAP3K7 mutation in a child with cardiospondylocarpofacial syndrome and orofacial clefting.

Here we present the case of a patient with a novel de novo, likely pathogenic, heterozygous MAP3K7 variant (c.528dupT, p.G177WfsX5) causing cardiospondylocarpofacial syndrome (CSCFS).

Dual BRCA1 and BRCA2 pathogenic variants in an adolescent with syndromic intellectual disability.

Pathogenic variants in the and genes are associated with increased risk for breast and ovarian cancers. Concurrent mutations in both genes in the same individual are rare but pose specific challenges when identified, usually through multigene panel testing or infrequently from a genome-wide analysis, such as whole-exome sequencing (WES). We present a 15-year-old female patient with syndromic intellectual disability whose exome reanalysis identified secondary findings of pathogenic and variants, both inherited paternally.

Pitfalls in Genetic Testing for Consanguineous Pediatric Populations.

We describe the diagnostic odyssey of an eight-year-old female born to consanguineous parents. Our patient presented with global developmental delay, regression, microcephaly, spastic diplegia, and leukodystrophy confirmed on brain magnetic resonance imaging (MRI). She was found on whole exome sequencing (WES) to have dual genetic diagnoses.

Genetic simulation for high-stakes conversations.

Background: High-stakes conversations are frequent in Medical Genetics. News shared is often perceived as "bad" and can lead to patient hostility. Breaking bad news (BBN) is therefore a challenging clinical task for physicians and is often included as a foundational skill in medical education.

mutation associated with severe myopia in a Canadian family.

Purpose: To describe a case of high myopia in a pediatric patient with a mutation in the gene and further characterize the diverse ocular phenotypes of heterozygous mutations.

Patient And Methods: We describe a three-year-old girl who presented at two months old with abnormal eye movements and suspected retinal dystrophy. Clinical exam and electroretinography (ERG) were conducted, and molecular next generation sequencing (NGS) with the Inherited Retinal Dystrophies panel was completed in our patient and offered to the family.

Role of matrix metalloproteinase MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP-1) in the clinical progression of pediatric acute lymphoblastic leukemia.

Background: Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and metastasis, however their role in pediatric Acute lymphoblastic leukemia (ALL) is still unrevealed.

Methods: The diagnostic, prognostic and predictive value of tissue inhibitor of metalloproteinase (TIMP-1), MMP-2, MMP-9 and CD34+CD38- cancer stem cells (CSCs) were assessed in bone marrow (BM) samples of 76 ALL children using Flow Cytometry analysis.

Results: There was a significant increase in TIMP-1 [1.

Resolving severe oligohydramnios as an early prenatal presentation of renal coloboma syndrome-A report of two generations.

This report suggests that self-resolving oligohydramnios is an early sign of malfunctioning kidney in individuals with renal coloboma syndrome (RCS) and demonstrates how a genetic diagnosis can impact patient and fetal management as it outlines two generations of RCS.

The phenotypic spectrum of AMER1-related osteopathia striata with cranial sclerosis: The first Canadian cohort.

Osteopathia striata with cranial sclerosis (OSCS; OMIM# 300373) is a rare X-linked disorder caused by mutations of the AMER1 gene. OSCS is traditionally considered a skeletal dysplasia, characterized by cranial sclerosis and longitudinal striations in the long bone metaphyses. However, OSCS affects many body systems and varies significantly in phenotypic severity between individuals.

Aromatase deficiency in an Ontario Old Order Mennonite family.

Objectives: Aromatase deficiency is a rare autosomal recessive disease that results in the absence of aromatase. In females it presents with ambiguous genitalia and lack of secondary sexual characteristics during puberty. Aromatase deficiency is not attributed to any specific population, but it is more commonly seen in consanguineous parents.

Clinical and technical assessment of MedExome vs. NGS panels in patients with suspected genetic disorders in Southwestern Ontario.

The adaptation of a broad genomic sequencing approach in the clinical setting has been accompanied by considerations regarding the clinical utility, technical performance, and diagnostic yield compared to targeted genetic approaches. We have developed MedExome, an integrated framework for sequencing, variant calling (SNVs, Indels, and CNVs), and clinical assessment of ~4600 medically relevant genes. We compared the technical performance of MedExome with the whole-exome and targeted gene-panel sequencing, assessed the reasons for discordance, and evaluated the added clinical yield of MedExome in a cohort of unresolved subjects suspected of genetic disease.

TP63-mutation as a cause of prenatal lethal multicystic dysplastic kidneys.

Background: Ectrodactyly-ectodermal dysplasia-clefting syndrome 3 (EEC) is one of the six overlapping syndromes caused by mutations in the tumor protein p63 gene (TP63). EEC is suspected when patients have cleft hands or feet, polydactyly, and syndactyly, abnormal development of the ectodermally derived structures, and orofacial clefting. Genitourinary (GU) anomalies have been identified in patients with EEC, yet these are often under-recognized and under-reported.

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained.

Challenges in Diagnosing Rare Genetic Causes of Common In Utero Presentations: Report of Two Patients with Mucolipidosis Type II (I-Cell Disease).

Traditional approaches to prenatal genetic diagnosis for common presentations such as short femurs or intrauterine growth restriction are imperfect, and whole-exome sequencing is an emerging option. Mucolipidosis type II (I-cell disease) is an ultra-rare autosomal recessive lysosomal storage disorder with the potential for prenatal-onset skeletal and placental manifestations. We describe the prenatal signs in two recent unrelated patients with confirmed diagnoses soon after birth.

Nonisolated diaphragmatic hernia in Simpson-Golabi-Behmel syndrome.

Objective: Congenital diaphragmatic hernia (CDH) is associated with Simpson-Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis.

Method: Retrospective review of 3 cases of SGBS type I in a single tertiary care centre.

Alagille syndrome: clinical perspectives.

Alagille syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae. Renal and vascular abnormalities can also occur. Inter- and intrafamilial variabilities in the clinical manifestations are common.

Brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: clinical presentation and anatomical distribution.

Background: Hereditary hemorrhagic telangiectasia is an autosomal dominant genetic disease with a wide array of vascular malformations involving multiple organs. Brain arteriovenous malformations can lead to intracranial hemorrhage and are often diagnosed only after patients become symptomatic. Early diagnosis and interventional treatment may prevent neurologic sequelae or death.

The possible role of cell cycle regulators in multistep process of HPV-associated cervical carcinoma.

Background: Human papillomavirus (HPV) 16 and 18 are associated with cervical carcinogenesis through an interaction between HPV oncogenic proteins and cell cycle regulatory genes. However, the exact pathogenetic mechanisms are not determined yet.

Methods: We investigated 43 invasive squamous cell carcinoma (ISCC), 38 CIN III, 11 CINII and 18 CINI for cyclin D1, cyclin E, CDK4, p53, mdm-2, p21(waf), p27, p16(INK4A), Rb and Ki-67 aberrations using immunohistochemistry and molecular techniques.