Congenital Myopathy via the HACD1 Gene

Congenital myopathy (CM) refers to a genetically and clinically heterogeneous group of disorders characterized by muscle weakness and hypotonia at birth or in infancy. Five forms of congenital myopathy are recognized by the International Standards of Care Committee for Congenital Myopathies (North et al. 2014. PubMed ID: 24456932): nemaline myopathy, core myopathy, centronuclear myopathy, myosin storage myopathy, and congenital fiber type disproportion. The clinical course of congenital myopathy is typically static or slowly progressive. Lower facial weakness leading to an open mouth is often the first sign of congenital myopathy in the newborn. Ptosis and ophthalmoplegia are also common. See North et al. (2014) for diagnostic strategies and a comprehensive review of the congenital myopathies.

HACD1-related congenital myopathy has been reported in only about 5 families to date. All of the affected individuals were either homozygous or compound heterozygous for HACD1 variants, with several being clear loss-of-function variants. Clinical features include generalized muscle weakness, hypotonia, feeding problems, delayed motor milestones, facial weakness, and, in some cases, cardiac findings (Abbasi-Moheb et al. 2021. PubMed ID: 33354762). Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the HACD1 gene are associated with autosomal recessive congenital myopathy. A splice variant, nonsense variant, missense variant, and 1250 bp LINE insertion in exon 6 have been reported in the HACD1 gene (Abbasi-Moheb et al. 2021. PubMed ID: 33354762; Al Amrani et al. 2020. PubMed ID: 32426512; Muhammad et al. 2013. PubMed ID: 23933735). To date, all pathogenic variants have been inherited from a carrier parent. No other large structural variants have been reported. HACD1 is relatively tolerant to loss of function variants (Genome Aggregation Database).

The HACD1 gene encodes 3-hydroxyacyl-CoA dehydratase 1, which is involved in the biosynthesis of very-long-chain fatty acids (VLCFAs). A SINE inserted in exon 2 of the canine HACD1 has been found to cause an autosomal recessive myopathy in Labrador retrievers, including hypotonia, generalized muscle weakness, reduced muscle mass, and exercise intolerance (Pelé et al. 2005. PubMed ID: 15829503). HACD1 has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

The clinical sensitivity is difficult to estimate as to date only a limited number of cases have been described in the literature (Abbasi-Moheb et al. 2021. PubMed ID: 33354762; Al Amrani et al. 2020. PubMed ID: 32426512; Muhammad et al. 2013. PubMed ID: 23933735). Analytical sensitivity should be high as almost all pathogenic variants reported to date are detectable by sequencing. A 1250 bp LINE insertion has been reported in exon 6 and it is uncertain if our NGS analysis would detect this variant (Al Amrani et al. 2020. PubMed ID: 32426512).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the HACD1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).