The article discusses the advancements and potential of long read sequencing (LRS) in genetic diagnostics, particularly in identifying structural variants and repeat expansions. Traditional genetic testing methods, such as cytogenetic techniques and short-read sequencing (SRS), have limitations in detecting certain genomic regions, especially repetitive and GC-rich sequences, leading to undiagnosed genetic disorders. LRS, with its ability to generate long reads and improved mappability, overcomes these limitations by providing more accurate and comprehensive detection of structural alterations and repeat expansions. The article highlights several clinical applications of LRS, including: 1. **Structural Variants (SVs)**: LRS has been shown to detect SVs more effectively than SRS, particularly in cases where SVs are located in repetitive or complex regions. Studies have demonstrated its utility in identifying undiagnosed Mendelian disorders and resolving ambiguous findings from SRS. 2. **Tandem Repeat-Related Diseases**: LRS can accurately map and size expanded tandem repeats, which are crucial for diagnosing diseases like dystrophinopathies and amyotrophic lateral sclerosis. It also allows for simultaneous detection of methylation status, providing additional diagnostic markers. 3. **Single Nucleotide Variants (SNVs)**: LRS can overcome the limitations of SRS in analyzing highly homologous sequences, such as pseudogenes, and can be used for haplotype phasing in autosomal recessive diseases. It has shown promise in detecting SNVs in genes with complex structures, such as *SMN1* in spinal muscular atrophy. 4. **Methylation Changes at Imprinted Genomic Regions**: LRS can simultaneously detect DNA sequence alterations and methylation changes, which is particularly useful in diagnosing imprinting disorders like Angelman syndrome and Prader-Willi syndrome. The article emphasizes the potential of LRS to improve diagnostic yields, reduce turnaround times, and enhance clinical management of genetic diseases. However, it also notes the need for further technological advancements and software development to fully realize the benefits of LRS in routine clinical practice.The article discusses the advancements and potential of long read sequencing (LRS) in genetic diagnostics, particularly in identifying structural variants and repeat expansions. Traditional genetic testing methods, such as cytogenetic techniques and short-read sequencing (SRS), have limitations in detecting certain genomic regions, especially repetitive and GC-rich sequences, leading to undiagnosed genetic disorders. LRS, with its ability to generate long reads and improved mappability, overcomes these limitations by providing more accurate and comprehensive detection of structural alterations and repeat expansions. The article highlights several clinical applications of LRS, including: 1. **Structural Variants (SVs)**: LRS has been shown to detect SVs more effectively than SRS, particularly in cases where SVs are located in repetitive or complex regions. Studies have demonstrated its utility in identifying undiagnosed Mendelian disorders and resolving ambiguous findings from SRS. 2. **Tandem Repeat-Related Diseases**: LRS can accurately map and size expanded tandem repeats, which are crucial for diagnosing diseases like dystrophinopathies and amyotrophic lateral sclerosis. It also allows for simultaneous detection of methylation status, providing additional diagnostic markers. 3. **Single Nucleotide Variants (SNVs)**: LRS can overcome the limitations of SRS in analyzing highly homologous sequences, such as pseudogenes, and can be used for haplotype phasing in autosomal recessive diseases. It has shown promise in detecting SNVs in genes with complex structures, such as *SMN1* in spinal muscular atrophy. 4. **Methylation Changes at Imprinted Genomic Regions**: LRS can simultaneously detect DNA sequence alterations and methylation changes, which is particularly useful in diagnosing imprinting disorders like Angelman syndrome and Prader-Willi syndrome. The article emphasizes the potential of LRS to improve diagnostic yields, reduce turnaround times, and enhance clinical management of genetic diseases. However, it also notes the need for further technological advancements and software development to fully realize the benefits of LRS in routine clinical practice.