Congenital asymmetric distal myopathy with hemifacial weakness caused by a heterozygous large de novo mosaic deletion in nebulin.
A substantial number of patients with rare inborn muscle disorders called nemaline myopathy and related disorders are still lacking molecular genetic confirmation of their diagnosis. In the present article, we described the identification of the first mosaic mutation, a deletion comprising exons 11-107, in the enormous nebulin gene. The deletion was identified using a copy number variation analysis based on data from next-generation sequencing
A substantial number of patients with rare inborn muscle disorders called nemaline myopathy and related disorders are still lacking molecular genetic confirmation of their diagnosis. Predicting the causative gene is difficult due to the clinically overlapping spectrum of nemaline myopathy and related disorders; the thirteen genes known to cause nemaline myopathy may cause other, clinically overlapping disorders also. Inheritance may be autosomal dominant or recessive, depending on the causative gene and type of mutation. Finding the molecular genetic cause is important for confirmation of the diagnosis and determining the mode of inheritance. Diagnostic clarity also serves as a basis for genetic counselling and future family planning.
One of the aims of the research project led by Drs. Wallgren-Pettersson and Pelin is to resolve the hitherto unknown genetic causes of nemaline myopathy, improve diagnostics and elucidate the molecular mechanisms leading from a mutated gene to muscle weakness, with the prospect of finding novel treatment options.
In the present article, we described the identification of the first mosaic mutation, a deletion comprising exons 11-107, in the enormous nebulin gene. The genetic term mosaic means that the mutation or variation is present in one of the alleles in some of the cells in the body, while in others, the normal allele is present in the usual two copies. The mutation was found to be present in a young Finnish woman presenting with a rather mild congenital myopathy and asymmetric muscle weakness, mainly affecting the distal parts of the extremities. She was able to walk. Muscle biopsies showed so-called myopathic features with predominance of slow type 1 fibres, strikingly small, fast type 2 fibres and centrally placed nuclei, instead of the usual location of the nuclei at the periphery of the muscle fibres. There were no nemaline bodies, although such bodies are often present in the muscle fibres of patients with nebulin mutations.
The deletion was identified using a copy number variation analysis based on data from next-generation sequencing. The parents of the patient did not carry the deletion. Mosaicism was detected using an in-house-designed comparative genomic hybridisation array. This method allows the quantification of copy numbers of the targeted regions in the genome. Expression of the shortened allele, less than half the size of full-length nebulin, was confirmed by immune (Western) blotting.
Original article:
Congenital asymmetric distal myopathy with hemifacial weakness caused by a heterozygous large de novo mosaic deletion in nebulin. Sagath L, Lehtokari VL, Välipakka S, Vihola A, Gardberg M, Hackman P, Pelin K, Jokela M, Kiiski K, Udd B, Wallgren-Pettersson C. Neuromuscul Disord. 2021 Jun;31(6):539-545. doi: 10.1016/j.nmd.2021.03.006. Epub 2021 Mar 23. PMID: 33933294