Genetic Breakthrough Pinpoints Causes of rare Neurodevelopmental Disorder
Table of Contents
- 1. Genetic Breakthrough Pinpoints Causes of rare Neurodevelopmental Disorder
- 2. Unraveling the Genetic Complexity
- 3. Mouse Model Mimics Human Condition
- 4. In vitro Studies Confirm Genetic Impact
- 5. The Role of Multilocus Variations
- 6. Understanding Neurodevelopmental Disorders
- 7. Frequently Asked Questions About Neurodevelopmental Disorders
- 8. What are the common neurodevelopmental phenotypes associated with biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5?
- 9. Unraveling the Genetic Complexity of Neurodevelopmental Disorders: Insights from Biallelic Loss-of-function Variants in TMEM141, DDHD2, and LHFPL5
- 10. The Expanding Landscape of Genetic Causes in Neurodevelopmental Conditions
- 11. TMEM141 and Early-Onset Neurodevelopmental Disorder
- 12. Clinical Features Associated with TMEM141 Variants
- 13. DDHD2: A Novel Gene in the Neurodevelopmental Spectrum
- 14. The Role of DDHD2 in brain Development
- 15. LHFPL5 and its Connection to Intellectual Disability and Movement Disorders
- 16. Understanding the LHFPL5-Related Neurodevelopmental Syndrome
Beijing, China – A groundbreaking study conducted by Researchers at the School of Basic Medicine, Peking Union Medical College, has revealed critical genetic factors contributing to a severe and complex neurodevelopmental disorder. The findings, recently published, shed light on the underlying causes of intellectual disability, spastic paraplegia, and deafness observed within a Pakistani family.
Unraveling the Genetic Complexity
Neurodevelopmental disorders pose a notable challenge to clinical genetics and medicine due to their intricate and varied presentation. Researchers emphasize the necessity of comprehensive genomic analysis to understand the relationship between genetic variations and observed clinical symptoms. The study focused on a family exhibiting a history of consanguinity-where parents are closely related-increasing the likelihood of inheriting identical copies of genes from both parents.
Through a meticulous process involving homozygosity mapping, SNP array analysis, and both whole-exome and whole-genome sequencing, the team identified homozygous variants in three specific genes: TMEM141, DDHD2, and LHFPL5. These genetic mutations are believed to be central to the development of the observed condition.
Mouse Model Mimics Human Condition
To further investigate the role of TMEM141,Researchers created a mouse model carrying the same genetic mutation found in the family. Behavioral assessments revealed significant impairments in learning and motor skills in the mice. Detailed analysis of brain tissue showed reduced synaptic plasticity in the hippocampus-a brain region vital for learning and memory-and atypical dendritic branching in the cerebellum, which is crucial for motor coordination.
Further examination using transmission electron microscopy displayed abnormal mitochondrial structure. Mitochondria are the powerhouses of cells, and their dysfunction can have widespread consequences. These findings suggest a link between the genetic mutation and impaired cellular energy production.
In vitro Studies Confirm Genetic Impact
To complement the animal model, Researchers conducted experiments using human neurons grown in a laboratory setting. By reducing the expression of TMEM141 in these cells, they observed a detrimental effect on bioenergetic function, potentially explaining the replicated symptoms seen in both the mouse model and the affected family members. This parallel evidence strengthens the conclusion that the identified genetic variations are directly linked to the neurodevelopmental disorder.
Did You Know? Approximately 1 in 50 children are affected by a neurodevelopmental disorder, highlighting the critical need for continued research in this field.
| Gene | Mutation | Associated Phenotype |
|---|---|---|
| TMEM141 | c.270G>A, p.Trp90* | Syndromic Intellectual Disability, impaired learning & motor skills |
| DDHD2 | c.411+767_c.1249-327del | Contributes to overall phenotype variability |
| LHFPL5 | c.250delC, p.Leu84* | Contributes to overall phenotype variability |
The Role of Multilocus Variations
The study underscores the importance of considering multiple gene variations when investigating complex disorders. Researchers concluded that the combined effect of variations in TMEM141, DDHD2, and LHFPL5 contributes to the diverse range of symptoms observed in the affected family.The biallelic loss-of-function variants specifically in TMEM141 are considered the primary driver of the syndromic intellectual disability.
Understanding Neurodevelopmental Disorders
Neurodevelopmental disorders are a diverse group of conditions affecting brain development, leading to challenges in learning, communication, and behavior. While genetic factors play a significant role, environmental influences are also believed to contribute. Early diagnosis and intervention are crucial to maximizing a childS potential. According to the CDC, the prevalence of neurodevelopmental disabilities in children has been steadily increasing in recent years, with approximately 17.8% of children aged 3-17 years being diagnosed with one or more of these conditions in 2022-2023.
Frequently Asked Questions About Neurodevelopmental Disorders
- What are neurodevelopmental disorders? These are conditions that affect the development of the brain and nervous system, impacting learning, behavior, and communication.
- Is intellectual disability always genetic? While genetics often play a role, intellectual disability can also result from environmental factors, injury, or illness.
- What is genomic variation analysis? This is a process of examining differences in an individual’s genome to identify potential causes of disease.
- How can a mouse model help with understanding human diseases? Mouse models allow Researchers to study disease mechanisms and test potential treatments in a controlled habitat.
- What is the significance of identifying multiple genes involved in a disorder? It highlights the complexity of these conditions and the need for comprehensive genetic analysis.
What other genetic factors could be contributing to similar neurodevelopmental conditions? How could these findings influence the development of targeted therapies?
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What are the common neurodevelopmental phenotypes associated with biallelic loss-of-function variants in TMEM141, DDHD2, and LHFPL5?
Unraveling the Genetic Complexity of Neurodevelopmental Disorders: Insights from Biallelic Loss-of-function Variants in TMEM141, DDHD2, and LHFPL5
The Expanding Landscape of Genetic Causes in Neurodevelopmental Conditions
Neurodevelopmental disorders (NDDs), encompassing conditions like autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy, represent a significant public health challenge.While environmental factors play a role, a substantial proportion of NDDs have a strong genetic basis. Recent advances in genomic sequencing technologies have dramatically increased our ability to identify causative genes, moving beyond single-gene disorders to unravel the complexity of polygenic and oligogenic contributions. Specifically, biallelic loss-of-function (LoF) variants – mutations that disrupt gene function – are emerging as critical players in several NDDs. This article focuses on three genes – TMEM141, DDHD2, and LHFPL5 – where biallelic LoF variants have been increasingly linked to neurodevelopmental phenotypes. Understanding these genetic underpinnings is crucial for improved diagnosis, genetic counseling, and potential therapeutic interventions. Key terms include neurogenetics,gene mutations,intellectual disability genes,and autism genetics.
TMEM141 and Early-Onset Neurodevelopmental Disorder
TMEM141 (Transmembrane Protein 141) was initially identified as a gene associated with early-onset, severe neurodevelopmental disorder with hypotonia, intellectual disability, and movement disorders. Biallelic LoF variants in TMEM141 are now recognized as a relatively common monogenic cause of this syndrome.
Clinical Features Associated with TMEM141 Variants
* Severe Hypotonia: Often present from birth, leading to feeding difficulties and delayed motor milestones.
* Global Developmental Delay: Significant delays across all developmental domains – cognitive,language,and motor skills.
* Intellectual Disability: Typically profound.
* Movement Disorders: Including dystonia, chorea, and ataxia.
* Seizures: Frequently observed, often refractory to standard anti-epileptic medications.
* Characteristic Facial Features: Subtle dysmorphic features may be present, aiding in clinical suspicion.
The protein encoded by TMEM141 is believed to be involved in neuronal migration and synaptic function. Loss of function disrupts these processes, leading to the observed neurological deficits. research suggests a link between TMEM141 and lysosomal function, highlighting a potential pathway for therapeutic targeting. Genetic testing for TMEM141 is now routinely included in diagnostic panels for severe early-onset NDDs.
DDHD2: A Novel Gene in the Neurodevelopmental Spectrum
DDHD2 (Dehydrogenase/Decarboxylase Homolog 2) is a more recently identified gene associated with neurodevelopmental disorders. Biallelic LoF variants in DDHD2 have been linked to a spectrum of phenotypes, ranging from mild intellectual disability to more severe presentations with autism-like features and epilepsy.
The Role of DDHD2 in brain Development
DDHD2 encodes a protein involved in lipid metabolism and signaling pathways crucial for brain development. Specifically, it plays a role in the metabolism of phosphatidylinositol, a key component of cell membranes. Disruption of this pathway can impact neuronal growth, synaptic plasticity, and overall brain structure.
* Autism Spectrum Disorder (ASD): A significant proportion of individuals with DDHD2 variants exhibit features consistent with ASD, including social communication deficits and repetitive behaviors.
* Intellectual Disability: Varying degrees of ID are commonly observed.
* Epilepsy: Seizures are a frequent feature, frequently enough presenting in early childhood.
* Behavioral Issues: Anxiety, hyperactivity, and attention deficits may also be present.
The phenotypic variability associated with DDHD2 variants underscores the complexity of genotype-phenotype correlations in NDDs. Whole exome sequencing (WES) and whole genome sequencing (WGS) are essential tools for identifying DDHD2 mutations.
LHFPL5 and its Connection to Intellectual Disability and Movement Disorders
LHFPL5 (Lipid Hydrogen Peroxide Glutathione Peroxidase 5) encodes an enzyme involved in protecting cells from oxidative stress. Biallelic lof variants in LHFPL5 have been associated with a distinct neurodevelopmental syndrome characterized by intellectual disability,movement disorders (notably dystonia),and cerebellar atrophy.
* Progressive Neurological Symptoms: Symptoms often emerge in early childhood and may worsen over time.
* Cerebellar Atrophy: A hallmark feature, detectable through brain MRI. This impacts coordination and balance.
* Dystonia: Sustained muscle contractions causing repetitive movements or abnormal postures.
* Intellectual disability: Typically moderate to severe.
* **Speech