De novo heterozygous variants in KIF5B cause kyphomelic dysplasia

Area of Science:

• Genetics and Molecular Biology
• Skeletal Dysplasias
• Human Disease Genetics

Background:

• Kyphomelic dysplasia is a rare skeletal disorder with limb bowing and variable features.
• The genetic causes of kyphomelic dysplasia remain largely unknown, necessitating further research.
• Kinesin motor proteins are crucial for intracellular transport, and their dysfunction can lead to various disorders (kinesinopathies).

Purpose of the Study:

• To identify the genetic basis of kyphomelic dysplasia in affected individuals.
• To characterize the phenotypic spectrum associated with identified genetic variants.
• To determine if KIF5B variants contribute to kyphomelic dysplasia and kinesinopathies.

Main Methods:

• Whole-exome sequencing was performed on four individuals diagnosed with kyphomelic dysplasia.
• Pathogenicity of identified variants in the KIF5B gene was evaluated.
• Clinical phenotypes were assessed and correlated with genetic findings.

Main Results:

• All four individuals presented with de novo heterozygous variants in KIF5B, encoding kinesin-1 heavy chain.
• The identified KIF5B variants were located in or near critical functional domains of the motor protein.
• Clinical manifestations included severe limb bowing, distinctive facial features, respiratory distress, short stature, osteoporosis, fractures, brachycephaly, and optic atrophy.

Conclusions:

• Deleterious heterozygous variants in KIF5B are a cause of a specific form of kyphomelic dysplasia.
• This study expands the known phenotypic spectrum of kinesinopathies.
• KIF5B mutations represent a significant genetic etiology for kyphomelic dysplasia.