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INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report
1Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350122, China.
Abstract:
Congenital muscular dystrophies (CMDs) are a genetically heterogeneous group of disorders. Variants in the INPP5K gene, which encodes a phosphoinositide phosphatase, are a rare cause of CMD. The condition is commonly associated with muscle weakness, early-onset cataracts, and intellectual disability, and prior reports have primarily identified missense, frameshift, or deletion variants. We describe the first Chinese case of INPP5K-related muscular dystrophy in a 28-year-old male with a mild phenotype, notably lacking intellectual disability. His presentation included bilateral cataracts at age 5 and adolescent onset limb girdle weakness. Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern of selective fatty infiltration, with severe involvement of gluteal and thigh muscles and striking sparing of the rectus femoris, sartorius, and gracilis. Genetic analysis identified compound heterozygous novel INPP5K variants: a missense c.274C>T, p.(Arg92Cys) and a synonymous c.261G>A, p.(Lys87=) change. Functional studies confirmed the synonymous variant causes aberrant splicing (exon 3 skipping), leading to a frameshift and premature termination p.(Leu52SerfsTer49). According to American College of Medical Genetics and Genomics guidelines, the c.274C>T and c.261G>A variants were classified as likely pathogenic and pathogenic, respectively. This first report of a Chinese patient with INPP5K-related muscular dystrophy broadens both the genetic and clinical spectrum of the disorder. We identify the first disease-causing synonymous variant (via aberrant splicing) and a novel hypomorphic missense variant p.(Arg92Cys), the combination of which explains the attenuated phenotype lacking intellectual disability. Our case highlights the critical role of RNA analysis in diagnosing non-canonical variants and confirms the universal diagnostic relevance of the characteristic muscle MRI pattern.
Insights
This study reports the first Chinese case of INPP5K-related muscular dystrophy, identifying novel genetic variants and a characteristic MRI pattern. The findings expand the understanding of this rare congenital muscular dystrophy and its associated phenotypes.
Area of Science:
- Genetics
- Neurology
- Biochemistry
Background:
- Congenital muscular dystrophies (CMDs) are a diverse group of genetic disorders affecting muscle development.
- INPP5K gene variants are a rare cause of CMD, typically presenting with muscle weakness, cataracts, and intellectual disability.
- Previous reports mainly identified missense, frameshift, or deletion variants in INPP5K.
Purpose of the Study:
- To describe the first Chinese case of INPP5K-related muscular dystrophy.
- To characterize the genetic variants and clinical phenotype, including muscle MRI findings.
- To investigate the functional impact of novel INPP5K variants.
Main Methods:
- Clinical assessment of a 28-year-old male with suspected CMD.
- Muscle magnetic resonance imaging (MRI) for detailed muscle evaluation.
- Genetic analysis (DNA sequencing) and RNA analysis to identify and characterize INPP5K variants.
- Functional studies to assess the impact of identified variants on gene splicing and protein function.
Main Results:
- A Chinese patient with a mild INPP5K-related muscular dystrophy phenotype, lacking intellectual disability, was identified.
- Novel compound heterozygous INPP5K variants were found: a missense (c.274C>T, p.(Arg92Cys)) and a synonymous (c.261G>A, p.(Lys87=)) variant.
- The synonymous variant led to aberrant splicing (exon 3 skipping), causing a frameshift and premature termination (p.(Leu52SerfsTer49)).
- Muscle MRI showed a distinct pattern of fatty infiltration, with gluteal and thigh muscle involvement and sparing of specific muscles.
Conclusions:
- This case expands the genetic and clinical spectrum of INPP5K-related muscular dystrophy.
- The first disease-causing synonymous variant via aberrant splicing and a novel hypomorphic missense variant were identified.
- The combination of variants explains the attenuated phenotype, highlighting the importance of RNA analysis for diagnosing non-canonical variants.
- The characteristic muscle MRI pattern is a valuable diagnostic tool for INPP5K-related muscular dystrophy.
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