KLHL40 – Nemaline Myopathy 8

Nemaline myopathy 8 (NEM8) is a severe autosomal recessive congenital myopathy caused by biallelic variants in the kelch-like family member 40 gene (KLHL40) and characterized by hypotonia, muscle weakness, joint contractures, fractures, respiratory failure and early mortality (MONDO:0014138). Genetic studies across diverse populations have identified numerous loss-of-function and missense variants implicating haploinsufficiency as the primary pathogenic mechanism.

Autosomal recessive inheritance is supported by multiple case reports and series. A Chinese-specific founder missense variant, c.1516A>C (p.Thr506Pro), was identified in six patients from five unrelated southern Chinese families ([PMID:32352246]). An additional five affected individuals from four independent Chinese pedigrees harbor a recurrent c.1516A>C (p.Thr506Pro) and other truncating or nonsense variants (e.g., c.543del (p.Ser182ProfsTer17), c.602G>A (p.Trp201Ter)) ([PMID:35379254]). A family with three affected siblings segregating a novel splice-site variant, c.1607+3A>T, further supports segregation in autosomal recessive transmission (3 affected relatives) ([PMID:39911178]). A single adult proband with compound heterozygous variants including a 10.9 kb deletion and a 3′ UTR splice-altering variant (c.*152G>T) expands the phenotypic spectrum to milder disease with later onset ([PMID:36322148]).

Segregation analysis in the splice-site family demonstrated co-segregation of c.1607+3A>T with disease in three affected members, confirming pathogenicity under a recessive model ([PMID:39911178]). Across studies, a total of 15 unrelated probands from 11 families have been reported with biallelic KLHL40 variants. Recurrent and founder alleles underscore the importance of population-specific screening strategies.

Clinically, affected individuals present with neonatal hypotonia (HP:0001252), generalized muscle weakness (HP:0001324), joint contractures, scoliosis and recurrent fractures. Prenatal signs include polyhydramnios (HP:0001561), decreased fetal movements (HP:0001558), breech presentation (HP:0001623) and talipes equinovarus (HP:0001762). Respiratory failure (HP:0002878) and dysphagia (HP:0002015) often necessitate early ventilatory support and feeding interventions.

Functional studies in zebrafish klhl40a mutants recapitulate key features of NEM8, including sarcomeric disorganization and muscle weakness, and global proteomic analyses reveal disrupted ubiquitin-mediated degradation pathways affecting thin filament and ER–Golgi trafficking proteins ([PMID:37432316]). The c.*152G>T 3′ UTR variant was shown by RNA sequencing and in vitro assays to induce de novo splicing events leading to nonsense-mediated decay and loss of protein expression ([PMID:36322148]). These data concordantly support a loss-of-function mechanism.

Integration of genetic and experimental evidence fulfills ClinGen criteria for a Strong gene–disease association. Pathogenic KLHL40 variants reliably predict NEM8 in patients with congenital myopathy, providing a basis for molecular diagnosis, carrier screening and early intervention. Key Take-home: KLHL40 variant analysis is essential for diagnosing NEM8 and guiding genetic counselling and management.

References

• Molecular genetics & genomic medicine • 2020 • The KLHL40 c.1516A>C is a Chinese-specific founder mutation causing nemaline myopathy 8: Report of six patients with pre- and postnatal phenotypes. PMID:32352246
• Molecular syndromology • 2025 • A Novel Splice Site Variant in KLHL40 Gene in Multiple Affected NEM8 Family Members Who Present Phenotypic Variability. PMID:39911178
• Journal of Human Molecular Genetics • 2023 • A KLHL40 3' UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism. PMID:36322148
• Molecular genetics & genomic medicine • 2022 • Homozygous or compound heterozygous variants in the KLHL40 gene cause nemaline myopathy 8: five individuals from four Chinese families. PMID:35379254
• eLife • 2023 • Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset. PMID:37432316

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