Objective: To elucidate the genetic cause in Pakistani families with recessively inherited disorders with dystonic features.

Background: Dystonia is a movement disorder characterized by sustained muscle contractions causing abnormal, often repetitive, movements and postures. Whereas a number of genetic causes of autosomal dominant dystonias have been identified, genes for recessive forms remain largely unknown. Recessive causes can best be elucidated in consanguineous families using next generation sequencing.

Methods: We collected six Pakistani consanguineous families with multiple affected individuals. Patients were videotaped and clinically examined by neurologists. We performed exome sequencing in 4-5 samples per family. Variants were filtered based on homozygosity in patients, predicted effect of variants on the encoded protein and their frequency in public databases. Segregation of candidate variants was tested in all available family members by Sanger sequencing.

Results: In Family RDHM-01, the disease was characterized by ataxia of gait, bradykinesia including hypomimia, mild dystonic postures of upper limbs, supranuclear gaze palsy, and spasticity with onset at the age of 1.5 year. In all four patients, we identified a novel, homozygous 1-basepair duplication (c.9119dup; p.Asn3040fs) in the SACS encoding sacsin, mutations in which caused spastic ataxia of the Charlevoix-Saguenay type. In Family RDHR-04, a homozygous 7-basepair deletion (c.599_605del; p.Pro200fs) was found in all five patients in ATCAY encoding caytaxin, mutations in which caused Cayman cerebellar ataxia. Our patients had severe gait ataxia, mild bibrachial dystonia, strabism, apraxia, and a suspicion of cognitive impairment with onset at the age of about 4 months. Finally, in Family RDHM-03, a homozygous missense mutation (c.551T>C; p.Ile184Thr) was found in MCOLN1 encoding mucolipin 1. Both patients in this family had adolescence onset generalized dystonia. Of note, mutations in MCOLN1 caused mucolipidosis IV, a neurodegenerative lysosomal storage disorder. None of the three mutations was found in 200 ethnically matched controls.

Conclusions: Exome sequencing is a powerful tool to detect disease-causing variants particularly in genes that would not be selected for diagnostic testing by Sanger sequencing.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exome-sequencing-reveals-homozygous-mutations-in-sacs-atcay-and-mcoln1-in-three-pakistani-families-with-complex-dystonia/