Advanced phasing techniques in congenital skin diseases

TL;DR

This paper reviews advanced phasing techniques using long-read sequencing for diagnosing and treating autosomal recessive skin diseases.

Contribution

The paper introduces novel phasing methods like nanopore Cas9-guided sequencing and adaptive sampling for complex clinical applications.

Findings

Low-coverage long-read sequencing improves haplotype determination in autosomal recessive diseases.

Nanopore sequencing aids in gene therapy design for recessive dystrophic epidermolysis bullosa.

Revertant mosaicism plays a role in therapeutic epidermal autografts.

Abstract

Phasing, the process of determining which alleles at different loci on homologous chromosomes belong together on the same chromosome, is crucial in the diagnosis and management of autosomal recessive diseases. Advances in long‐read sequencing technologies have significantly enhanced our ability to accurately determine haplotypes. This review discusses the application of low‐coverage long‐read sequencing, nanopore Cas9‐guided long‐read sequencing, and adaptive sampling in phasing, highlighting their utility in complex clinical scenarios. Through clinical vignettes, we explore the importance of phasing in gene therapy design for recessive dystrophic epidermolysis bullosa and the role of revertant mosaicism in therapeutic epidermal autografts. Despite its promise, phasing with long‐read sequencing faces challenges, including low efficiency in enriching target regions and the inherent error rate of nanopore sequencing. Future developments in long‐read sequencing technologies will be critical in overcoming these limitations and expanding the applicability of phasing across various clinical settings.

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