Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Pleiotropy01:33

Pleiotropy

40.5K
Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
40.5K
Lethal Alleles02:41

Lethal Alleles

15.4K
Agouti: A Lethal Allele
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
15.4K
Incomplete Dominance01:43

Incomplete Dominance

22.6K
Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.
22.6K
X-linked Traits01:19

X-linked Traits

54.9K
In most mammalian species, females have two X sex chromosomes and males have an X and Y. As a result, mutations on the X chromosome in females may be masked by the presence of a normal allele on the second X. In contrast, a mutation on the X chromosome in males more often causes observable biological defects, as there is no normal X to compensate. Trait variations arising from mutations on the X chromosome are called “X-linked”.
54.9K
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

4.8K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
4.8K
Multiple Allele Traits01:49

Multiple Allele Traits

34.2K
The Concept of Multiple Allelism
34.2K

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing.

medRxiv : the preprint server for health sciences·2026
Same author

Astrocytes contribute to olanzapine-mediated reversal of Kleefstra Syndrome-associated neurodevelopmental regression.

The Journal of clinical investigation·2026
Same author

Direct and indirect regulation of fetal globin transcript by RNA-binding protein IGF2BP1.

Blood·2026
Same author

Automated reanalysis of genomic data for rare disease diagnostics at scale.

Nature medicine·2026
Same author

RNU4ATAC-opathy: Clinical, molecular and transcriptomic insights from a large cohort.

Genetics in medicine : official journal of the American College of Medical Genetics·2026
Same author

Hereditary cancer: Germline testing practices across ERN GENTURIS member countries.

European journal of human genetics : EJHG·2026

Related Experiment Video

Updated: Jul 4, 2025

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
00:06

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

13.7K

Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features.

Morad Ansari1, Kamli N W Faour2, Akiko Shimamura3

  • 1South East Scotland Genetic Service, Western General Hospital, Edinburgh, UK; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

HGG Advances
|February 1, 2024
PubMed
Summary

Loss-of-function variants in the SMC3 gene cause variable developmental phenotypes, including intellectual disability and growth issues, expanding the understanding of cohesinopathies. These findings highlight SMC3 as a haploinsufficient gene with significant population-level intolerance to loss-of-function mutations.

Keywords:
CdLS3Cornelia de Lange syndromeLoFSMC3cohesinloss-of-function

More Related Videos

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
09:37

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

Published on: August 15, 2019

9.7K
In Vivo Modeling of the Morbid Human Genome using Danio rerio
12:31

In Vivo Modeling of the Morbid Human Genome using Danio rerio

Published on: August 24, 2013

20.7K

Related Experiment Videos

Last Updated: Jul 4, 2025

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
00:06

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

13.7K
Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
09:37

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information

Published on: August 15, 2019

9.7K
In Vivo Modeling of the Morbid Human Genome using Danio rerio
12:31

In Vivo Modeling of the Morbid Human Genome using Danio rerio

Published on: August 24, 2013

20.7K

Area of Science:

  • Genetics
  • Developmental Biology
  • Human Genetics

Background:

  • Heterozygous missense variants and in-frame indels in SMC3 cause Cornelia de Lange syndrome (CdLS) via a dominant-negative mechanism.
  • The phenotypic spectrum of SMC3 loss-of-function (pLoF) variants remained largely uncharacterized, prompting investigation into alternative phenotypes or lethality.

Purpose of the Study:

  • To characterize the clinical manifestations and mutational intolerance associated with heterozygous predicted loss-of-function (pLoF) variants in the SMC3 gene.
  • To compare the phenotypes of individuals with SMC3 pLoF variants to those with missense/in-frame indel variants.

Main Methods:

  • Identification of individuals with SMC3 pLoF variants using matchmaking servers and patient registries.
  • Analysis of population databases to assess mutational intolerance of the SMC3 gene.
  • Phenotypic analysis of affected individuals and comparison with existing CdLS cohorts.

Main Results:

  • SMC3 is highly constrained against pLoF variants, indicating strong haploinsufficiency.
  • Individuals with SMC3 pLoF variants exhibited variable phenotypes including growth parameters, developmental delay/intellectual disability, and dysmorphism, resembling atypical CdLS.
  • SMC3 pLoF variants were associated with milder presentations compared to missense/in-frame indel variants, with instances of nonpenetrance and alternative symptomatologies.

Conclusions:

  • SMC3 functions as an archetypal haploinsufficient gene, with pLoF variants leading to a spectrum of developmental phenotypes.
  • The study expands the understanding of cohesinopathies and their allelic architecture, suggesting other LoF-intolerant genes may be implicated in developmental disorders.
  • Multilayered genomic data and careful phenotyping are crucial for confirming disease links in LoF-constrained genes.