A family’s medical mystery sheds light on the surprising ways disease-causing genes can be inherited

A family’s medical mystery sheds light on the surprising ways disease-causing genes can be inherited

Publication date: Jul 09, 2019

-We could hear her screaming as soon as the elevator opened,” Lana Legkiy, Tatiana’s mother, there treated Tatiana and started medication that helped her heart pump.

Along the way, researchers would uncover an undiagnosed heart problem in Tatiana’s older sister, provide a new explanation for why Lana lost a prior pregnancy, and shed light on the unexpected ways in which disease-causing mutations can be inherited.

Tatiana; her older sister, Anna; and the lost fetus each received rare mutations in three genes from their parents – two from their father, one from their mother – that together triggered the heart issues.

-Each one of these, it pushes you a little closer to the cliff, until the point you get pushed off the cliff,” said Dr. Wendy Chung, a pediatric geneticist at Columbia University Medical Center, who was not part of the team studying the Legkiy family.

Tatiana in 2009 Courtesy Lana LegkiyTatiana arrived at the hospital over a decade ago, but the scientific quest only culminated recently, when a team of researchers from the Gladstone Institutes and the University of California, San Francisco, published a paper in Science laying out how they had teased apart exactly what was going on.

Their discoveries were only possible because of advances in stem cell and genome editing wizardry that didn’t exist when Tatiana was born, and because of the encounter with a family whose children had all inherited the same confluence of mutations.

If only one of the children had had the heart issues, -you would never recognize that as a genetic cause,” said Dr. Deepak Srivastava, the president of Gladstone and a pediatric cardiologist at UCSF Benioff Children’s Hospital, who was one of the clinicians involved in Tatiana’s care years ago.

In 2014, while searching for disease-influencing variants of genes involved in the development of the heart, the team landed on three in the MKL2, MYH7, and NKX2-5 genes that Andrey and Lana’s three children all had.

MYH7 plays a key role in the contraction of the heart, while the other two genes help choreograph the formation of the heart during development.

The Legkiy family Courtesy Lana Legkiy-Each of these genes, their function is disrupted in a given number of cells, but each one only causes a slight level of disruption,” said Casey Gifford, a Gladstone scientist and the lead author of the paper.

Researchers not involved with the investigation praised the work, noting just how many steps were required – and how long it took – to corroborate the genetic roots of the heart conditions.

Concepts Keywords
Ambulance RTT
Anemia Medicine
California Branches of biology
Cardiologist Scientific search answers
Chicago Diseases
Childrens Hospital Contraction
Cliff Congenital heart defect
Columbia Center Mutation
Confluence Genetic disorder
Congenital Heart Problems MYH7
CRISPR Wendy Chung
Cystic Fibrosis Fabry disease
Dallas
Echocardiogram
Elevator
Embryonic Development
Exomes
Ferret
Fetus
Gene
Genetic
Geneticist
Genome
Genome Editing
Gladstone
Hospital
Left Ventricular
Lost Weeks
Modesto
Mutation
MYH7
Mystery
Pediatric
Pediatrician
Pluripotent
Pregnancy
San Francisco
Sequencing
Sickle
Syndrome
The Catch
UCSF

Semantics

Type Source Name
gene UNIPROT FBXW7
gene UNIPROT EHD1
disease MESH fetus
disease MESH cystic fibrosis
disease DOID cystic fibrosis
disease DOID sickle cell anemia
disease MESH sickle cell anemia
gene UNIPROT NAA50
disease MESH emergency
disease DOID left ventricular noncompaction
gene UNIPROT CNOT8
disease MESH Bardet-Biedl syndrome
disease DOID Bardet-Biedl syndrome
gene UNIPROT AIFM2
gene UNIPROT TNFSF14
disease MESH congenital
gene UNIPROT BAD
gene UNIPROT NKX2-5
gene UNIPROT MYH7
gene UNIPROT MRTFB
disease MESH development
gene UNIPROT LITAF
disease MESH abnormalities
gene UNIPROT REST

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