Publications by authors named "Zackai E"
The 22q11.2 Deletion Syndrome (22q11.2DS) is a multisystem genetic disorder with prominent sleep disturbances, neuropsychiatric conditions and neurocognitive challenges.
View Article and Find Full Text PDFObjectives: Hearing loss is considered common in children with 22q11.2 deletion syndrome (22q11.2DS), with a few prior studies reporting a 32%-78% prevalence; mild-moderate conductive hearing loss has been reported most commonly.
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- Zinc and RING finger 3 (ZNRF3) regulates Wnt/β-catenin signaling, crucial for brain development, but germline variants have not been linked to neurodevelopmental disorders (NDDs) before.
- Researchers found 12 individuals with ZNRF3 variants, noting a correlation between specific mutations and NDD phenotypes, especially those affecting brain size.
- Structural modeling and functional assays revealed that missense variants linked to larger brain size enhanced Wnt signaling, while a variant causing smaller brain size reduced it, indicating different mechanisms at play in NDDs related to ZNRF3 mutations.
Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2.
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- This study investigates secondary findings (SFs) from clinical next-generation sequencing in a large pediatric group, including many African-American participants, focusing on their types and frequencies.
- It uses specific criteria to identify pathogenic and likely pathogenic variants in established genes, assessing their potential health impacts on participants.
- The results reveal a total of 1464 pathogenic variants identified in over 16,700 participants, with notable frequencies in both ACMG and non-ACMG genes, such as TTR and CHEK2.
Purpose: Hardikar syndrome (HS, MIM #301068) is a female-specific multiple congenital anomaly syndrome characterized by retinopathy, orofacial clefting, aortic coarctation, biliary dysgenesis, genitourinary malformations, and intestinal malrotation. We previously showed that heterozygous nonsense and frameshift variants in MED12 cause HS. The phenotypic spectrum of disease and the mechanism by which MED12 variants cause disease is unknown.
View Article and Find Full Text PDFExome sequencing (ES) has emerged as an essential tool in the evaluation of neurodevelopmental disorders (NDD) of unknown etiology. Genome sequencing (GS) offers advantages over ES due to improved detection of structural, copy number, repeat number and non-coding variants. However, GS is less commonly utilized due to higher cost and more intense analysis.
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- KMT2C and KMT2D are important enzymes that modify genes, with KMT2C haploinsufficiency recently linked to Kleefstra syndrome 2, a neurodevelopmental disorder (NDD) with unknown clinical details.
- A study involving 98 individuals found that most pathogenic variants in KMT2C span nearly all its exons, making variant interpretation difficult; the study also established a KMT2C DNA methylation signature for better classification of the disorder.
- Key features of KMT2C-related NDD include developmental delays, intellectual disabilities, and distinct facial characteristics, setting it apart from similar conditions like Kleefstra and Kabuki syndromes, indicating the need for its renaming and
Background: Minor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders.
View Article and Find Full Text PDFImportance: Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years.
Objectives: To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD.
Design, Setting, And Participants: This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital.
Article Synopsis
- Meningomyelocele is a serious neural tube defect and the most common structural birth defect affecting the central nervous system.
- The Spina Bifida Sequencing Consortium found that deletions on chromosome 22q11.2 increase the risk of meningomyelocele by 23 times compared to the general population.
- Research indicates that the deletion of specific genes in this region, combined with a lack of maternal folate, can significantly increase the risk of neural tube defects in offspring.
Article Synopsis
- The study evaluates the use and effectiveness of genetic testing in diagnosing infants with esophageal atresia (EA) and tracheoesophageal fistula (TEF) over a 12-year period to improve future care and management.
- It involves a retrospective analysis of 212 infants, identifying different classifications (complex/syndromic, isolated/nonsyndromic) and noting varying success rates for different genetic tests performed.
- The findings suggest that EA/TEF has a complex genetic landscape, highlighting the need for advanced testing methods like exome sequencing to better understand its causes and improve diagnosis.
Background: Enlarged cavum septum pellucidum (CSP) and hypoplastic thymus are proposed extra-cardiac fetal markers for 22q11.2 deletion syndrome. We sought to determine if they were part of the fetal phenotype of our cohort of fetuses with 22q11.
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- - Over the past 50-60 years, genetics and dysmorphology have become essential in medicine, helping diagnose rare diseases and informing various medical specialties.
- - Both fields heavily depend on molecular geneticists for identifying genes linked to disorders, showcasing their interconnectedness in patient care.
- - The memoirs collected highlight the personal journeys of professionals in these specialties, emphasizing their adaptability and the chance experiences that led them to enjoy a career in genetics and dysmorphology.
Background: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in-person assessment can be unavailable or burdensome.
View Article and Find Full Text PDFPrevious research suggests that individuals with 22q11.2 deletion syndrome (DS) have an increased risk of bleeding following cardiac surgery. However, current guidelines for management of patients with 22q11.
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- - The study explores pre-mRNA splicing, its critical role in neurodevelopment, and how mutations in spliceosome-related genes U2AF2 and PRPF19 contribute to neurodevelopmental disorders (NDDs).
- - Researchers found multiple pathogenic variants in U2AF2 and PRPF19 across unrelated individuals, with functional analysis showing that specific U2AF2 variants disrupted normal splicing and neuritogenesis in human neurons.
- - Additionally, investigations in Drosophila models revealed that the loss of function in U2AF2 and PRPF19 caused severe developmental defects and social issues, pointing to a genetic network wherein splicing factors like Rbfox1 play a significant role in brain development and function. *
Article Synopsis
- The 22q11.2 deletion syndrome is a genetic condition that's common and often linked to heart problems. Prenatal testing for this condition is becoming more common.
- This study looked at how well babies do when they are diagnosed before they are born versus after they are born.
- They found that, overall, the chance of dying in the first year didn't change much between those diagnosed early or late, but serious heart problems and when the baby was born affected the results.
Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels.
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- Recurrent 17q12 deletions are linked to various clinical issues, primarily affecting kidney and urinary tract development, diabetes, and neurodevelopmental disorders, with structural renal disease noted as the most common feature.
- A study of 26 cases with identified 17q12 microdeletions, particularly in 17 cases with prenatal ultrasound findings, revealed diverse kidney issues such as renal cysts and echogenic kidneys.
- The research suggests using genetic testing for 17q12 microdeletions in cases of renal anomalies detected before birth, as this information can significantly impact management during pregnancy and after birth due to differing prognoses.
Article Synopsis
- NR2F2 (also known as COUP-TF2) is a transcription factor crucial for mammalian development, with rare variants linked to conditions like congenital heart disease (CHD) and congenital diaphragmatic hernia (CDH).
- This study reviews 17 new cases of individuals with heterozygous NR2F2 variants, confirming variability in clinical features, such as intrauterine growth restriction, heart defects, developmental delays, and various congenital anomalies.
- The findings showcase the need for better characterization of the phenotypic range associated with NR2F2 variants and potential clinical guidelines for diagnosis and evaluation.
Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS).
View Article and Find Full Text PDFBackground: Children undergoing complex cardiac surgery are exposed to substantial cumulative doses of sedative medications and volatile anesthetics and are more frequently anesthetized with ketamine, compared with healthy children. This study hypothesized that greater exposure to sedation and anesthesia in this population is associated with lower neurodevelopmental scores at 18 months of age.
Methods: A secondary analysis was conducted of infants with congenital heart disease who participated in a prospective observational study of environmental exposures and neurodevelopmental outcomes to assess the impact of cumulative volatile anesthetic agents and sedative medications.
Article Synopsis
- Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder marked by a variety of symptoms including growth delays, upper limb issues, and other systemic problems, primarily caused by mutations in specific genes associated with the cohesin complex.
- The majority of CdLS cases (over 60%) are linked to mutations in the NIPBL gene, which leads to the most severe form of the syndrome; other cohesin gene mutations typically result in milder symptoms.
- The study analyzed the genetic factors in 716 individuals with CdLS to better understand the contributions of cohesin complex genes and identify potential new candidate genes, improving knowledge of genetic variations and their effects on CdLS manifestations.