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The genetic basis of disease

Affiliations.

• 1 School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
• 2 School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K. [email protected].
• 3 School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
• PMID: 30509934
• PMCID: PMC6279436
• DOI: 10.1042/EBC20170053
• Correction: The genetic basis of disease. Jackson M, Marks L, May GHW, Wilson JB. Jackson M, et al. Essays Biochem. 2020 Oct 8;64(4):681. doi: 10.1042/EBC20170053_COR. Essays Biochem. 2020. PMID: 32720679 Free PMC article. No abstract available.

Genetics plays a role, to a greater or lesser extent, in all diseases. Variations in our DNA and differences in how that DNA functions (alone or in combinations), alongside the environment (which encompasses lifestyle), contribute to disease processes. This review explores the genetic basis of human disease, including single gene disorders, chromosomal imbalances, epigenetics, cancer and complex disorders, and considers how our understanding and technological advances can be applied to provision of appropriate diagnosis, management and therapy for patients.

Keywords: cancer; genetics; genomics; molecular basis of health and disease.

© 2018 The Author(s).

PubMed Disclaimer

Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figure 1. Some types of variants found…

Figure 1. Some types of variants found in human genomes

Variation involving one or a…

Figure 2. Giemsa banding (G-banding) to form…

Figure 2. Giemsa banding (G-banding) to form a karyogram

( A ) Metaphase spreads like…

Figure 3. Chromosome structure and band nomenclature

This ideogram of the complete chromosome 8 illustrates…

Figure 4. Principles of meiosis and non-disjunction

For simplicity, only one pair of newly replicated…

Figure 5. Fertilisation outcomes

( A ) Fertilisation of a normal oocyte with a normal…

Figure 6. Segregation of reciprocal translocations

( A ) A carrier of a reciprocal translocation…

Figure 7. The X and Y chromosomes…

Figure 7. The X and Y chromosomes determine male or female sexual development

Males produce…

Figure 8. Schematic map of the X…

Figure 8. Schematic map of the X and Y chromosomes

The X and Y chromosomes…

Figure 9. The XIC

A simplified view…

A simplified view of genes located at the XIC (not to…

Figure 10. Autosomal dominant inheritance and pedigree

( A ) Inheritance pattern of an autosomal…

Figure 11. Autosomal recessive inheritance and pedigree

Figure 12. X-linked recessive inheritance and pedigree

( A ) Inheritance pattern of an X-linked…

Figure 13. Insertions and deletions

( 1 ) A wild-type sequence consisting of three-letter words.…

Figure 14. CF symptoms depend on residual…

Figure 14. CF symptoms depend on residual CFTR activity

The left-hand side shows a scale…

Figure 15. Mitochondrial structure

The mitochondrion has…

The mitochondrion has two membranes; the inner membrane folds into series…

Figure 16. The electron transport chain

On the inner membrane of the mitochondria, electrons from…

Figure 17. The mitochondrial genome

Circular and…

Circular and double stranded, with no introns, the mitochondrial genome…

Figure 18. Mitochondrial inheritance

In the case…

In the case of a mitochondrial mutation (see following section), an…

Figure 19. Heteroplasmy

A primordial germ cell…

A primordial germ cell containing a mixture of mutant and normal mtDNA…

Figure 20. Mitochondrial replacement therapy (‘three-parent baby’)

Eggs are harvested ( 1 ) from the…

Figure 21. Methylation of cytosine and consequences…

Figure 21. Methylation of cytosine and consequences of deamination of methyl-C

( A ) Cytosine…

Figure 22. Methylation occurs on the C…

Figure 22. Methylation occurs on the C of the sequence CG and facilitates binding of…

Figure 23. Methylation and demethylation

The methylation…

The methylation process is initiated by addition of a methyl…

Figure 24. DNA methylation status is heritable…

Figure 24. DNA methylation status is heritable but requires maintenance

( A ) The Cs…

Figure 25. Chromatin status is influenced by…

Figure 25. Chromatin status is influenced by DNA methylation and histone acetylation

In active chromatin…

Figure 26. Imprints are erased and reset…

Figure 26. Imprints are erased and reset during gametogenesis

For each imprinted chromosome region, healthy…

Figure 27. Imprinting on chromosome 15

A cluster of genes near the centromere of chromosome…

Figure 28. The principles of genetic association

SNP1 (with alleles C and T) and SNP2…

Figure 29. Genome wide association study for…

Figure 29. Genome wide association study for T2D-related loci

Appropriate study groups are selected from…

Figure 30. Many factors, environmental, genetic and…

Figure 30. Many factors, environmental, genetic and epigenetic interact together in the overall risk for…

Figure 31. Different cancer types typically display…

Figure 31. Different cancer types typically display different numbers of mutations in the cell genome

Figure 32. Cancer increases with age

Theoretical…

Theoretical cancer incidence curves are shown reflecting a set…

Figure 33. Signal transduction

The cell receives…

The cell receives signals from contact with other cells, from the…

Figure 34. A simplified, typical signal transduction…

Figure 34. A simplified, typical signal transduction pathway

Many growth factors (secreted proteins) interact with…

Figure 35. Oncogenic mutations

Examples of oncogene…

Examples of oncogene activating mutations are depicted. ( A ) Gene…

Figure 36. RAS activation

( A ) RAS is bound to GDP in the inactive…

Figure 37. The cell cycle and RB

The cell cycle is depicted, showing the phases…

Figure 38. Sensing and responding to damaged…

Figure 38. Sensing and responding to damaged DNA

The proteins that initiate DNA repair after…

Figure 39. FISH

( A ) One or more fluorescently labelled probes are required for…

Figure 40. Allele-specific PCR by positioning the…

Figure 40. Allele-specific PCR by positioning the variant at the 3′ end of one primer

Figure 41. The MLPA assay and application…

Figure 41. The MLPA assay and application to diagnosis of DGS

( A ) Short…

Figure 42. Automated Sanger sequencing

( A ) PCR products ( 1 ) are generated…

Figure 43. QF-PCR

Several microsatellite loci (here…

Several microsatellite loci (here R, S and T) on the relevant chromosome(s)…

Figure 44. Selecting an appropriate test

Where the pathogenic variant in a family is known…

Figure 45. Basic microarray

The microarray (…

The microarray ( 1 ) is a grid of hundreds of…

Figure 46. SNP array data can reveal…

Figure 46. SNP array data can reveal copy number imbalance and homozygosity associated with consanguinity…

Figure 47. SNP array demonstrates areas of…

Figure 47. SNP array demonstrates areas of loss and gain across the genome at high…

Figure 48. NGS data analysis

The screenshots…

The screenshots cover one exon from the analysis of a…

Figure 49. Amniocentesis procedure

Under ultrasound guidance,…

Under ultrasound guidance, a thin needle is passed through the abdominal…

Figure 50. NIPD for trisomy 21

( A ) Foetal cell-free DNA (cfDNA) from the…

Figure 51. Pre-implantation genetic diagnosis by biopsy…

Figure 51. Pre-implantation genetic diagnosis by biopsy of early embryos

Traditional IVF procedures ( 1…

Figure 52. EGFR mutation status determines the…

Figure 52. EGFR mutation status determines the outcome of erlotinib as a therapy

Figure 53. EGFR mutation status must be…

Figure 53. EGFR mutation status must be determined in order to ensure that erlotinib is…

Figure 54. Potential therapeutic approaches for DMD

( A ) In healthy muscle the dystrophin…

Figure 55. The use of CRISPR/Cas9 in…

Figure 55. The use of CRISPR/Cas9 in DMD

In stem cells from the patient CRISPR/Cas9…

Figure 56. Cost per genome over time

As a comparison, expected fall in cost as…

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2022: a pivotal year for diagnosis and treatment of rare genetic diseases

The start of 2022 is an inflection point in the development of diagnostics and treatments for rare genetic diseases in prenatal, pediatric, and adult individuals–the theme of this special issue. Here I briefly review recent developments in two pivotal aspects of genetic disease diagnostics and treatments: education and equitable implementation.

The start of 2022 is an inflection point in the development of diagnostics and treatments for rare genetic diseases in prenatal, pediatric, and adult individuals—the theme of this special issue. We now know the molecular basis of more than 7100 genetic diseases ( https://www.omim.org/statistics/geneMap ). International data sharing and genomic sequencing are greatly accelerating the identification of new, ultra-rare disorders ( Osmond et al. 2022 ). We can diagnose a critically ill child with a genetic disease by rapid whole-genome sequencing (WGS) in only 7 h ( Gorzynski et al. 2022 ). More than 500 childhood-onset genetic diseases have at least somewhat effective treatments ( Owen et al. 2022 ; http://gtrx.rbsapp.net ). Timely diagnosis by rapid WGS in critically ill newborns can save organs and lives with interventions as simple as dietary supplements ( Owen et al. 2021 ). Real-world health-care economic studies have shown that rapid WGS in regional intensive care units can save several thousand dollars per patient tested if turnaround time is short ( Dimmock et al. 2021 ). A research-grade, 30-fold coverage genome sequence now costs <$400 to generate, either by short-read sequencing-by-synthesis or long-read nanopore DNA sequencing ( https://www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-Costs-Data ). A patient-specific genetic therapy can be made from scratch and first administered within 13 mo ( Kim et al. 2019 ). As noted in a recent editorial, rapid WGS in critically ill children has shifted from unease to evidence, education, and equitable implementation ( Franck et al. 2021 ). Here I briefly review recent developments in the latter two aspects of rare genetic disease diagnostics and treatments.

EQUITABLE IMPLEMENTATION OF GENOMIC MEDICINE

Unfortunately, much remains to be done to implement genomic medicine equitably. We are thankfully witnessing the demise of unenlightened policies that only cover outpatient genetic testing. Formerly, U.S. physicians were required to discharge ill children with suspected genetic diseases from hospital to order outpatient molecular testing that their health-care insurance would cover. The idiocy of this policy was exemplified in a recent study that found a sevenfold higher diagnostic rate with inpatient WGS compared with outpatient WGS ( Thiffault et al. 2019 ).

I will never forget my first meeting with Sir Mark Caulfield, then the Chief Scientist of Genome England, in the early 2010s. I mentioned the need for further quantitative studies of the clinical utility and cost effectiveness of rapid WGS in hospitalized infants to accelerate reimbursement discussions. He declared that there was already sufficient evidence and the need, instead, was national implementation. Such thinking spurred the U.K. Secretary of State for Health and Social Care, Matt Hancock, to announce in 2018 that the National Health Service would be the first to provide diagnostic WGS to all seriously ill children with a suspected genetic disorder ( https://www.genomicsengland.co.uk/matt-hancock-announces-5-million-genomes-within-five-years/ ). Happily, this will also be policy in Germany in 2023 ( https://dejure.org/gesetze/SGB_V/64e.html ). In the United States, the first coverage policy for inpatient, diagnostic, rapid WGS was written by Bob Plass, Medical Director of Blue Shield—California in 2019 ( https://www.blueshieldca.com/bsca/bsc/public/common/PortalComponents/provider/StreamDocumentServlet?fileName=PRV_WholeExome_Sequen.pdf ). His criteria for assessing when rapid exome or rapid WGS, with trio testing when possible, should be considered medically necessary for the evaluation of infants or children in intensive care with illness of unknown etiology, are excellent. Anthem, Blue Cross, and Blue Shield have since ratified this policy nationally. Genomic equity is starting to happen in the United States. Medicaid, the joint federal and state program that provides health coverage to nearly all low-income Americans, including children, pregnant women, parents, seniors, and individuals with disabilities, is the largest source of health coverage in the United States. In 2018, California Assembly members Brian Maienschein and Rob Bonta, cochairs of the California Legislative Rare Disease Caucus, sponsored a bill that funded Project Baby Bear, a real-world implementation project of diagnostic, rapid WGS in critically ill Medicaid infants in five children's hospitals ( Dimmock et al. 2021 ). Baby Bear was a success. It demonstrated that the clinical utility and cost effectiveness of rapid diagnostic WGS observed in research studies could be recapitulated in routine care in Medicaid infants ( Dimmock et al. 2021 ). In response, the California legislature passed bills to make rapid diagnostic WGS a covered Medicaid benefit and provided funds to cover hospital costs of testing. Although this became policy in 2022, the California Department of Health authorized no reimbursement separate from the existing Diagnosis Related Group (DRG) payment to offset the incremental costs for hospitals to provide this new service ( https://files.medi-cal.ca.gov/pubsdoco/bulletins/artfull/ips202112.aspx ). Because Medicaid reimburses only 90% of the costs of hospital care, Medicaid beneficiaries in California still lack equitable access ( https://www.aha.org/fact-sheets/2020-01-07-fact-sheet-underpayment-medicare-and-medicaid ). In contrast, an almost identical project in Michigan, Project Baby Deer, resulted in a policy decision in 2021 by the Michigan Department of Health that authorized rapid diagnostic WGS with reimbursement separate from the DRG payment to hospitals ( https://www.michigan.gov/documents/mdhhs/MSA_21-33_732848_7.pdf ). Similar Baby Manatee and Baby Bambi implementation projects are in progress in Florida ( https://www.floridatrend.com/article/32113/nicklaus-childrens-hospital-project-baby-manatee-advanced-genomics-cuts-diagnostic-delays-costs ) and Israel ( https://www.gov.il/en/departments/news/21102021-03 ). Finally, the “Precision Medicine Answers for Kids Today” provisions of the Cures 2.0 Act recently reintroduced to Congress would greatly accelerate equitable implementation in the United States ( https://www.congress.gov/bill/117th-congress/house-bill/6000/text ).

GENOMIC MEDICINE EDUCATION

For new entrants to the field of genome-informed medicine it is important to point out that rapid diagnostic WGS sequencing was not possible until 2012 ( Saunders et al. 2012 ), and the first effectiveness study of this method was not published until 2014 ( Soden et al. 2014 ). Because it takes a minimum of 10 years to train a medical subspecialist, we are still awaiting an influx of consultants whose formal training included genomic medicine. Medical textbooks, a definitive source of medical information, do not yet cover the topic of intravenous fluid replacement adequately, never mind genomic medicine, leading physicians at the University of Glasgow to lament: “Systematic revision of current textbooks might improve knowledge and practice by junior doctors. Careful definition of the remit and content of textbooks should be applied more widely to ensure quality, fitness for purpose, and avoid omission of vital knowledge” ( Powell et al. 2014 ; Tez and Yildiz 2017 ). In the interim, while genomic medicine curricula are designed and textbooks rewritten, education of health-care providers is occurring by bootstrapping. Several such methods are proving effective. One is multidisciplinary, case-based learning that engages health-care professionals in the process of making real-world patient decisions. We have been doing this almost weekly for 5 years ( https://radygenomics.org/education ). Initially case-based learning was in-person. For the last 3 years, however, it has been wholly virtual—enabling unanticipated expansion to diverse, global audiences. The format is simple. A physician starts by presenting a recent case, sharing pertinent clinical findings in the order in which they were ascertained. The presentation is interactive, with participants asking branching questions. Case-based learning is a pedagogical approach that relies on a core premise of medical training: the use of our clinical knowledge, acumen, and experience to formulate a temporally dynamic list of differential diagnoses in every patient seen. Getting that list “right” and correctly ordered, predicated on the net prior probability of each disorder in each patient is considered a criterion of clinical excellence. For those who are not physicians, this is evidenced by searching PubMed for “formulating a differential diagnosis,” which returns more than 1500 references or, alternatively, by watching 177 episodes of House, M.D. In unstable patients, empiric therapy is started immediately. As test results are received, new features evolve, and responses to empiric treatment are observed, the Bayesian diagnostician recomputes net posterior probabilities and reorders the list.

Next in case-based learning, a laboratory director presents the diagnostic genome sequencing results, together with information regarding the genetic, pathologic, and clinical features of the disorder. When teaching, it is vitally important to avoid jargon and to provide a glossary of specialist terms and synonyms. It can be disheartening to be told, “It's called a variant not a mutation.” Again, discussion follows. Last, a physician presents the treatment regimen, patient response, and outcome. The latter is important because it is very motivating for health-care learners. Final discussion occurs. The vital knowledge conveyed to health-care learners by case-based learning is rather simple: Rapid, comprehensive, diagnostic genomic sequencing is indicated early in the evaluation of all severely ill infants and children in whom the underlying etiology of illness is uncertain, and later in the evaluation of patients who are not responding typically to empiric treatment . The beautiful new reality is that rapid whole-genome sequencing is increasingly being regarded as a homogeneous test to diagnose (or help rule out) 7100 disorders ( Dimmock et al. 2020 ). Hitherto this concept was restricted to the tricorder on Star Trek ( Chan et al. 2019 )!

Another bootstrapping method for equipping frontline physicians in the practice of genomic medicine is the provision of web-based, artificial-intelligence-assisted, clinical decision support tools. For diagnosis, these include Phenomizer and PubCaseFinder ( Köhler et al. 2009 ; Fujiwara et al. 2018 ). At pediatric grand rounds at Children's Mercy Hospital 10 years ago, I would enter clinical features of cases being discussed in Phenomizer on my cell phone and then impishly suggest ultra-obscure differential diagnoses that the hapless chief resident was unable to spell. One of the successes of this young journal has been to illustrate repeatedly the humbling phenomenon of phenotype expansion—new presentations of known genetic diseases that require fuzzy rather than Boolean logic in diagnostic decision support tools. Dr. Kristen Newby calls such cases the hoofbeats of colored zebras ( Halle and Andrews 1986 ). Physician-selected descriptors of childhood genetic disease cases only overlap 3% of the clinical features of their genome sequencing–based diagnosis ( Clark et al. 2019 ). Natural language processing of electronic health records (EHRs) can improve this fit fivefold ( Clark et al. 2019 ). Phenotype expansion and its antecedent—very incomplete knowledge of the breadth of clinical presentations of childhood genetic diseases—are major reasons that focused tests are increasingly being replaced by disorder-agnostic WGS. Clinical decision support tools can help medicine escape the mindset of the fabled drunkard, who limited the search for his lost car key to under the lamppost because that was where the light was ( Collins 2006 ). Eric Topol has admonished that we need to expose doctors to artificial intelligence–based diagnostic tools and help them understand clinical features that are not recorded in the EHR cannot be computed ( Topol 2019 ). Artificial intelligence, paradoxically, may drive a renaissance in recording a complete history and physical signs in the EHR. Another, newer type of clinical decision support tool that is emerging for rare genetic disease is in therapy guidance. Systems such as Genome-to-Treatment help alleviate the unsupportable burden of searching and synthesizing the published treatment literature in rare genetic disease cases, many of which frontline physicians may have never encountered previously ( Owen et al. 2022 ).

The year 2022 will be important in the development of diagnostics and treatments for rare genetic diseases in prenatal, pediatric, and adult individuals. This perspective did not do justice to the breadth of clinical decision support tools, implementation projects, or legislative coverage decisions that are underway. Please write to me with details of those I missed, and I will update this piece. Meanwhile, in the words of Fred Lyons, “The children are waiting” ( https://scholarlyexchange.childrensmercy.org/cgi/viewcontent.cgi?article=1003&context=recent_history ).

ADDITIONAL INFORMATION

Acknowledgments.

Many thanks to Hilger Ropers, Elaine Mardis, Wendy Benson, and Russell Nofsinger for suggestions that greatly improved this perspective. A Deo lumen, ab amicis auxilium .

S.F.K. is supported by research grants from the National Institutes of Health (NIH) (U01TR002271 to J.M. Davis and J.L. Maron, U54TR002359 to E.J. Topol, and R01HD101540 to S.F.K. and C.D. Chambers), Takeda, and Rady Children's Hospital.

Competing Interest Statement

The author has declared no competing interest.

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Genetic Disorders

Many human diseases have a genetic component. Some of these conditions are under investigation by researchers at or associated with the National Human Genome Research Institute (NHGRI).

A genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence. Genetic disorders can be caused by a mutation in one gene (monogenic disorder), by mutations in multiple genes (multifactorial inheritance disorder), by a combination of gene mutations and environmental factors, or by damage to chromosomes (changes in the number or structure of entire chromosomes, the structures that carry genes). As we unlock the secrets of the human genome (the complete set of human genes), we are learning that nearly all diseases have a genetic component. Some diseases are caused by mutations that are inherited from the parents and are present in an individual at birth, like sickle cell disease. Other diseases are caused by acquired mutations in a gene or group of genes that occur during a person's life. Such mutations are not inherited from a parent, but occur either randomly or due to some environmental exposure (such as cigarette smoke). These include many cancers, as well as some forms of neurofibromatosis.

List of Genetic Disorders

This list of genetic, orphan and rare diseases is provided for informational purposes only and is by no means comprehensive.

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Scientists' research on RNA editing illuminates possible lifesaving treatments for genetic diseases

by Reagan Cotton, Montana State University

A team at Montana State University published research this month that shows how RNA, the close chemical cousin to DNA, can be edited using CRISPRs. The work reveals a new process in human cells that has potential for treating a wide variety of genetic diseases.

Postdoctoral researchers Artem Nemudryi and Anna Nemudraia conducted the research alongside Blake Wiedenheft, professor in the Department of Microbiology and Cell Biology in MSU's College of Agriculture. The paper, titled "Repair of CRISPR-guided RNA breaks enables site-specific RNA excision in human cells ," was published online on April 25 in the journal Science and constitutes the latest advance in the team's ongoing exploration of CRISPR applications for programmable genetic engineering.

CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is a type of immune system that bacteria use to recognize and fight off viruses. Wiedenheft, one of the nation's leading CRISPR researchers, said that the system has been used for years to cut and edit DNA, but that applying similar technology to RNA is unprecedented.

DNA editing uses a CRISPR-associated protein called Cas9, while editing RNA requires the use of a different CRISPR system, called type-III.

"In our previous work, we used type-III CRISPRs to edit viral RNA in a test tube," said Nemudryi. "But we wondered, can we program manipulation of RNA in a living human cell?"

To explore that question, the team programmed type-III CRISPR proteins to cut RNA containing a mutation that causes cystic fibrosis, restoring cell function.

"We were confident that we could use these CRISPR systems to cut RNA in a programmable manner, but we were all surprised when we sequenced the RNA and realized that the cell had stitched the RNA back together in a way that removed the mutation," said Wiedenheft.

Nemudryi noted that RNA is transient within the cell; it is constantly being destroyed and replaced.

"The general belief is that there's not much point in repairing RNA," he said. "We speculated that RNA would be repaired in living human cells, and it turned out to be true."

Wiedenheft has mentored the two postdoctoral researchers since their arrival at MSU nearly six years ago, and said that the impact of their scientific contributions will lead to significant and continued advancements.

"The work done by Artem and Anna suggests that RNA repair might be a fundamental aspect of biology and that harnessing this activity may lead to new lifesaving cures," said Wiedenheft. "Artem and Anna are two of the most brilliant scientists I have ever encountered, and I'm confident that their work is going to have a lasting impact on humanity."

RNA editing has important applications in the search for treatments of genetic diseases, Nemudryi said. RNA is a temporary copy of a cell's DNA, which serves as a template. Manipulating the template by editing DNA could cause unwanted and potentially irreversible collateral changes, but because RNA is a temporary copy, he said, edits made are essentially reversible and carry far less risk.

"People used Cas9 to break DNA and study how cells repair these breaks. Then, based on these patterns, they improved Cas9 editors," said Nemudraia. "Here, we hope the same will happen with RNA editing. We created a tool that allows us to study how the cells repair their RNA, and we hope to use this knowledge to make RNA editors more efficient."

In the new publication, the team shows that a mutation causing cystic fibrosis can be successfully removed from the RNA. But this is only one of thousands of known mutations that cause disease. The question of how many of them could be addressed with this new RNA editing technology will guide future work for Nemudryi and Nemudraia as they finish their postdoctoral training at MSU and prepare for faculty positions at the University of Florida this fall. Both credited Wiedenheft as a life-changing mentor.

"Blake taught us not to be afraid of testing any ideas," said Nemudraia. "As a scientist, you should be brave and not be afraid to fail. RNA editing and repair is the terra incognita. It's scary but also exciting. You feel you're working on the edge of science, pushing the limits to where nobody has been before."

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• Tier 1 applications are supported by synthesized evidence or evidence-based recommendations for implementation in practice. More than 150 guidelines have been classified as tier 1.
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Researchers find a single, surprising gene behind a disorder that causes intellectual disability

Scientists have found the genetic root of a disorder that causes intellectual disability, which they estimate affects as many as one in 20,000 young people

Scientists have found the genetic root of a disorder that causes intellectual disability, which they estimate affects as many as one in 20,000 young people. And they hope their discovery leads to a new diagnosis that can provide answers to families.

Those with the condition have a constellation of issues, which also include short stature, small heads, seizures and low muscle mass, said the researchers, who published their findings in the journal Nature Medicine on Friday.

“We were struck by how common this disorder is" when compared with other rare diseases linked to a single gene, said Ernest Turro of the Icahn School of Medicine at Mount Sinai, senior author of the study.

Syndromes like these can go unnoticed because the traits are sometimes so subtle doctors can’t recognize them by just looking at patients, said Dr. Charles Billington, a pediatric geneticist at the University of Minnesota who was not involved in the study.

“So certainly this wasn’t something that we necessarily had a name for," he said. “We’re learning more about these syndromes that we recognize only once we are seeing the cause.”

Researchers said the mutations occurred in a small “non-coding” gene, meaning it doesn’t provide instructions for making proteins. Until now, all but nine of the nearly 1,500 genes known to be linked to intellectual disability in general are protein-coding genes. Most large genetic studies so far have used a sequencing technology that typically leaves out genes that don't code for proteins.

This study used more comprehensive “whole-genome” sequencing data from 77,539 people enrolled in the British 100,000 Genomes Project, including 5,529 with an intellectual disability. The rare mutations researchers found in the gene, called RNU4-2, were strongly associated with the potential to develop intellectual disability.

The finding “opens the door to diagnoses” for thousands of families, said study author Andrew Mumford, research director of the South West England NHS Genomic Medicine Service.

More research is needed, Mumford said. How the mutation causes the disorder remains unclear and there is no treatment. But Billington said labs should be able to offer testing for this condition relatively quickly. And researchers said families should be able to find and support each other – and know they’re not alone.

“That can be incredibly comforting,” Mumford said.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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Researchers find a single, surprising gene behind a disorder that causes intellectual disability

FILE - This microscope image shows the 46 human chromosomes, blue, with telomeres appearing as white pinpoints. Scientists have found the genetic cause of a neurodevelopmental disorder that they estimate affects as many as one in 20,000 young people. And they hope their discovery leads to a new diagnosis that can provide answers to families. They published their findings in the journal Nature Medicine on Friday (Hesed Padilla-Nash, Thomas Ried/National Cancer Institute/National Institutes of Health via AP, File)

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Scientists have found the genetic root of a disorder that causes intellectual disability, which they estimate affects as many as one in 20,000 young people. And they hope their discovery leads to a new diagnosis that can provide answers to families.

Those with the condition have a constellation of issues, which also include short stature, small heads, seizures and low muscle mass, said the researchers, who published their findings in the journal Nature Medicine on Friday.

“We were struck by how common this disorder is” when compared with other rare diseases linked to a single gene, said Ernest Turro of the Icahn School of Medicine at Mount Sinai, senior author of the study.

Syndromes like these can go unnoticed because the traits are sometimes so subtle doctors can’t recognize them by just looking at patients, said Dr. Charles Billington, a pediatric geneticist at the University of Minnesota who was not involved in the study.

“So certainly this wasn’t something that we necessarily had a name for,” he said. “We’re learning more about these syndromes that we recognize only once we are seeing the cause.”

Researchers said the mutations occurred in a small “non-coding” gene, meaning it doesn’t provide instructions for making proteins. Until now, all but nine of the nearly 1,500 genes known to be linked to intellectual disability in general are protein-coding genes. Most large genetic studies so far have used a sequencing technology that typically leaves out genes that don’t code for proteins.

This study used more comprehensive “whole-genome” sequencing data from 77,539 people enrolled in the British 100,000 Genomes Project, including 5,529 with an intellectual disability. The rare mutations researchers found in the gene, called RNU4-2, were strongly associated with the potential to develop intellectual disability.

The finding “opens the door to diagnoses” for thousands of families, said study author Andrew Mumford, research director of the South West England NHS Genomic Medicine Service.

More research is needed, Mumford said. How the mutation causes the disorder remains unclear and there is no treatment. But Billington said labs should be able to offer testing for this condition relatively quickly. And researchers said families should be able to find and support each other – and know they’re not alone.

“That can be incredibly comforting,” Mumford said.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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