Revisiting LSDMCA: male lethality escape and genotype-phenotype correlations.

Area of Science:

• Genetics
• Developmental Biology
• Biochemistry

Background:

• Mitochondrial disorders (MDs) affect cellular energy production via the oxidative phosphorylation (OXPHOS) system.
• Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA), or Microphthalmia with Linear Skin Lesions (MLS) syndrome, is a rare, X-linked dominant, male-lethal disorder.
• Existing knowledge of genotype-phenotype correlations in LSDMCA is limited.

Purpose of the Study:

• To identify novel genetic variants associated with LSDMCA.
• To broaden the understanding of the phenotypic spectrum and genotype-phenotype correlations in LSDMCA.
• To investigate the role of mitochondrial dysfunction in LSDMCA pathogenesis.

Main Methods:

• Whole exome sequencing (WES) was performed on three patients diagnosed with LSDMCA.
• Novel pathogenic variants in HCCS, COX7B, and NDUFB11 genes were identified.
• Functional studies were conducted to assess the impact of identified variants on mitochondrial respiratory chain (MRC) function.

Main Results:

• Three novel pathogenic variants were identified: missense variants in HCCS and COX7B, and a frameshift variant in NDUFB11.
• Functional studies confirmed that the identified COX7B variant impairs mitochondrial respiratory chain (MRC) function.
• A male patient (46, XY) with a COX7B variant survived, suggesting that certain mild variants may permit male survival in LSDMCA.

Conclusions:

• The findings expand the known genetic causes and phenotypic spectrum of LSDMCA.
• Mitochondrial dysfunction plays a significant role in the pathogenesis of LSDMCA.
• Mildly impairing variants may alter the male lethality associated with this X-linked disorder, expanding the phenotype.