News Article | April 18, 2016
Thanks in part to the efforts of one dedicated mother, who took to Facebook to document her son’s mysterious developmental disability, an international team of researchers led by scientists at UC San Francisco and Baylor College of Medicine in Houston has now identified a new genetic syndrome that could help illuminate the biological causes of one of the most common forms of intellectual disability. In a study of 10 children published online in the American Journal of Human Genetics on April 14, the researchers linked a constellation of birth defects affecting the brain, eye, ear, heart and kidney to mutations in a single gene, called RERE. The discovery is likely to aid researchers striving to understand the cause of birth defects more broadly, the study’s authors said, but it is also a boon to families who know for the first time the reason their children share this group of developmental disabilities. “Just having an answer can be hugely beneficial for families,” said co-senior author Elliott Sherr, M.D., Ph.D., a UCSF pediatric neurologist who directs the Brain Development Research Program and the Comprehensive Center for Brain Development at UCSF. “Of course, getting a genetic answer is just the first step, but for the longest time we didn’t even have that much. It gives these families hope that we can move forward.” Finding could speed search for answers in more common genetic syndrome In their paper, the researchers demonstrate that the developmental disabilities suffered by children with RERE mutations correspond almost perfectly to the well-known pattern of intellectual disabilities, heart defects, craniofacial abnormalities, and hearing and vision problems seen in 1p36 deletion syndrome, one of the most common sources of intellectual disability in children. This syndrome occurs in approximately 1 in 5,000 newborns, and is caused by a much larger (and harder to study) pattern of genetic damage in the so-called 1p36 region at the tip of human chromosome 1. The research group of Daryl Scott, MD, PHD, an associate professor of molecular and human genetics at Baylor College of Medicine, has been working for many years to identify the specific genes that cause the medical problems in children with 1p36 deletion syndrome. “Previous research had narrowed it down to two smaller ‘critical regions’ within the 1p36 region, but even these smaller regions contain dozens of different genes,” said Scott, who was co-senior author on the new study. Scott’s group had focused on the RERE gene, which lies within one of these 1p36 critical regions, because it plays a role in retinoic acid (vitamin A) signaling, an important pathway regulating the development of many organs, including the brain, eye and heart. The Baylor researchers found that mice with Rere mutations had birth defects that were very similar to the children with 1p36 deletions, but had initially been unable to prove that damage to this gene was sufficient produce the same developmental problems in humans. Sherr and Scott credit the genesis of their collaboration to Chauntelle Trefz, the mother of one of Sherr’s patients who connected the two researchers after discovering Scott’s work on mice with Rere mutations online and whose Facebook page about her son, Harrison, became a hub for identifying other children with the same condition. Trefz says that getting the whole exome sequencing results from Sherr and learning that a single gene mutation was responsible for her son’s dizzying array of symptoms — which include global developmental delay, vision problems, hearing problems, weak muscles, and constant acid reflux — was “a game-changer.” “Learning about the mutation was like a huge weight had been lifted,” she said. “When you bring a child with special needs into the world you feel so guilty, like you’ve done something wrong. Hope can be a hard thing to find. Dr. Sherr gave us hope.” Trefz started a Facebook page documenting the joys and challenges of raising and caring for Harrison, who is now 4, hoping to find other families whose children had the same condition. “Harrison is such a happy kid, and he seems normal in many ways, but he’s really not,” she said. “I could see a lot of kids falling through the cracks without the right diagnosis. I wanted other parents to see this and say, ‘that sounds like my son.’” Soon Sherr and Scott had identified 10 children with RERE mutations through collaborators around the US, as well as several from the Netherlands who had found the researchers through Trefz’s Facebook page. The researchers began a thorough comparison of these 10 children with a cohort of 31 patients with the more common 1p36 deletion syndrome, and found that RERE mutations alone produced almost exactly the same pattern of symptoms as 1p36 syndrome, with the exception of a few of the craniofacial abnormalities and cardiomyopathies often seen in that more common syndrome. Additional experiments showed that unique brain and eye problems first observed in human patients were also seen in the mice with Rere mutations. “It’s still a shock that [a mutation in] one gene is capable of causing all these different problems,” Scott said. “But this finding really brings everything together, from molecular studies to mouse experiments and all the way to human patients. We’ve finally proved what we’ve been talking about for all these years.” Though much more study is needed to understand the syndrome fully, Scott said, RERE mutations may be capable of inducing a diverse set of developmental problems because the protein encoded by the gene interacts with important developmental processes in many organs throughout the body, such as the retinoic acid signaling crucial for proper eye and heart development. When RERE doesn’t function properly, the development of all of these organs is affected. Sherr acknowledges that the current sample of just 10 patients with RERE mutations, who each experience slightly different symptoms with notably different levels of severity, is too small to give a complete portrait of the new syndrome. “Now that we’ve seen the first 10 cases, we want to know what the next 10, the next 20 look like,” he said. “That may not take very long. Before we’d even published the paper, we’d already gotten calls from more clinics around the country whose patients have similar mutations. We suspect this syndrome may be significantly more common than we previously appreciated.” The empowerment of families through social media and the plummeting cost of of gene sequencing technologies have produced a revolution in the pace of discovery about rare genetic conditions, Sherr said. “In the last five years alone there’s been a huge explosion in the number of conditions we can decipher genetically – we can take a few kids with developmental disabilities, come up with a coherent genetic explanation for what has happened and use that as first step for how to move forward” he said. “When I started working in child neurology as a fellow back in the late ‘90s, we understood just a few of these super-rare genetic disorders but now there are hundreds. And we’re just getting started.” The authors acknowledge the following industry ties: Sherr is a member of the clinical advisory board of genetic testing company InVitae and consults for Personalis. Four of the authors are employees of GeneDx, which provides exome sequencing on a clinical basis. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical laboratory testing conducted at Baylor Miraca Genetics Laboratories, which provides exome sequencing on a clinical basis.
Yuan B.,Baylor College of Medicine |
Yuan B.,Baylor Miraca Genetics Laboratories |
Liu P.,Baylor College of Medicine |
Liu P.,Baylor Miraca Genetics Laboratories |
And 2 more authors.
Genomics Data | Year: 2016
Array comparative genomic hybridization (aCGH) has been widely used to detect copy number variants (CNVs) in both research and clinical settings. A customizable aCGH platform may greatly facilitate copy number analyses in genomic regions with higher-order complexity, such as low-copy repeats (LCRs). Here we present the aCGH analyses focusing on the 45 kb LCRs  at the NPHP1 region with diverse copy numbers in humans. Also, the interspecies aCGH analysis comparing human and nonhuman primates revealed dynamic copy number transitions of the human 45 kb LCR orthologues during primate evolution and therefore shed light on the origin of complexity at this locus. The original aCGH data are available at GEO under GSE73962. © 2016 The Authors. Source
Westerfield L.E.,Baylor College of Medicine |
Stover S.R.,Baylor College of Medicine |
Mathur V.S.,Baylor College of Medicine |
Nassef S.A.,Baylor College of Medicine |
And 6 more authors.
Prenatal Diagnosis | Year: 2015
Objective: Diagnostic whole exome sequencing (WES) is rapidly entering clinical genetics, but experience with reproductive genetic counseling aspects is limited. The purpose of this study was to retrospectively review and report on our experience with preconception and prenatal genetic counseling for diagnostic WES. Method: We performed a retrospective chart review over 34months in a large private prenatal genetic counseling practice and analyzed data for referral indications, findings, and results of genetic counseling related to diagnostic WES. Results: Ten of 14 patients counseled about diagnostic WES for ongoing pregnancies pursued the test, resulting in identification of three pathogenic variants (30%). Five of 15 patients seeking counseling about familial WES results in an affected proband pursued prenatal diagnosis, resulting in identification of one affected fetus and five unaffected fetuses. We experienced challenges related to complexity and uncertainty of results, turnaround time, cost and insurance overage, and multidisciplinary fetal care coordination. Conclusion: Despite having experienced complexity and identified challenges of the reproductive genetic counseling, availability of diagnostic WES contributed important information that aided in prenatal care planning and decision-making. Future enhanced provider education and larger studies to systematically study the integration of WES in reproductive genetic counseling and prenatal care will be important. © 2015 John Wiley & Sons, Ltd. Source
Zhang J.,Mount Sinai School of Medicine |
Zhang J.,Baylor College of Medicine |
Lachance V.,Mount Sinai School of Medicine |
Schaffner A.,Mount Sinai School of Medicine |
And 27 more authors.
PLoS Genetics | Year: 2016
Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway. © 2016 Zhang et al. Source
Pupavac M.,McGill University |
Tian X.,Baylor Miraca Genetics Laboratories |
Chu J.,McGill University |
Wang G.,Baylor Miraca Genetics Laboratories |
And 11 more authors.
Molecular Genetics and Metabolism | Year: 2016
Next generation sequencing (NGS) based gene panel testing is increasingly available as a molecular diagnostic approach for inborn errors of metabolism. Over the past 40 years patients have been referred to the Vitamin B12 Clinical Research Laboratory at McGill University for diagnosis of inborn errors of cobalamin metabolism by functional studies in cultured fibroblasts. DNA samples from patients in which no diagnosis was made by these studies were tested by a NGS gene panel to determine whether any molecular diagnoses could be made. 131 DNA samples from patients with elevated methylmalonic acid and no diagnosis following functional studies of cobalamin metabolism were analyzed using the 24 gene extended cobalamin metabolism NGS based panel developed by Baylor Miraca Genetics Laboratories. Gene panel testing identified two or more variants in a single gene in 16/131 patients. Eight patients had pathogenic findings, one had a finding of uncertain significance, and seven had benign findings. Of the patients with pathogenic findings, five had mutations in ACSF3, two in SUCLG1 and one in TCN2. Thus, the NGS gene panel allowed for the presumptive diagnosis of 8 additional patients for which a diagnosis was not made by the functional assays. © 2016 Elsevier Inc.. Source