ClinVar Genomic variation as it relates to human health

Polyhydramnios (present) , Abnormal delivery (present) , Gestational diabetes (present) , Ventouse delivery (present) , Open mouth (present) , Macrocephaly (present) , Epicanthus (present) , Triangular face (present) , Low-set ears (present) , Wide nasal bridge (present) , Horizontal nystagmus (present) , Delayed speech and language development (present) , Global developmental delay (present) , Hypertonia (present) , Generalized hypotonia (present) , Dystonic disorder (present) , Tremor (present) , Brisk reflexes (present) , Frontal bossing (present) , Bradykinesia (present) , Intention tremor (present) , Broad-based gait (present) , Drooling (present) , Resting tremor (present) , Diffuse cerebral atrophy (present) , Parkinsonism with favorable response to dopaminergic medication (present) , Decreased muscle mass (present) , Bruxism (present) , Involuntary movements (present) , Decreased body weight (present) , Chiari type I malformation (present) , Loud snoring (present) (less)

Mitochondrial Neurodevelopmental Disorder with Abnormal Movements and Lactic Acidosis and without Seizures For discussion of the c.37T-G transversion (c.37T-G, NM_201263.2) in the WARS2 gene, resulting in a trp13-to-gly (W13G) substitution, that was found in compound heterozygous state in 2 sisters with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis and without seizures (NEMMLAS; 617710) by Musante et al. (2017), see 604733.0001. Childhood-Onset Parkinsonism-Dystonia 3 In a 17-year-old boy with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738), Burke et al. (2018) identified compound heterozygous missense mutations in the WARS2 gene: a W13G substitution in exon 1, affecting the mitochondrial localization signal, and a c.683C-G transversion in exon 6, resulting in a ser228-to-trp (S228W; 604733.0008) substitution in the tryptophan-tRNA ligase domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. W13G was present in the ExAC database with an allelic frequency of 0.0034 and was not predicted to be extremely deleterious, whereas S228W was not present in ExAC. Western blot analysis of patient cells showed a marked decrease in steady-state levels of WARS2 compared to controls. Patient skeletal muscle biopsy showed mild mitochondrial abnormalities, although OXPHOS activity was normal; the authors postulated that mitochondrial dysfunction contributed to nigrostriatal degeneration. The patient had onset of levodopa-responsive parkinsonism at about 2 years of age; the disorder was progressive. In a 31-year-old man with PKDYS3, Hubers et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: W13G and a c.149G-A transition, resulting in a gly50-to-asp (G50D; 604733.0009) substitution. The mutations, which were found by trio-based exome sequencing, segregated with the disorder in the family. W13G was found 9 times in the homozygous state in the gnomAD database, consistent with it being a hypomorphic allele and only disease-causing when combined with a more deleterious allele. G50D was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed. The patient developed a severe hyperkinetic movement disorder in the first years of life; he also had cognitive defects and could communicate nonverbally on a basic level. Brain imaging showed cerebellar atrophy. He did not have seizures, which may have explained his long survival. In 6 patients from 4 unrelated families with PKDYS3, Skorvanek et al. (2022) identified compound heterozygous mutations in the WARS2 gene. All patients carried a W13G variant on 1 allele. Two sibs from family 1 had a deletion of exon 2 on the other allele (604733.0011). Fibroblasts derived from these patients showed decreased levels of full-length WARS2 protein compared to controls. Two sibs from family 2 carried leu100del (604733.0004) on the other allele; functional studies were not performed. The patient from family 3 carried G50D (604733.0009) on the other allele; functional studies were not performed. The patient from family 4 carried a c.622G-T transversion, resulting in a glu208-to-ter (E208X; 604733.0012) substitution on the other allele; functional studies were not performed, but it was predicted to result in premature termination. (less)

Mitochondrial Neurodevelopmental Disorder with Abnormal Movements and Lactic Acidosis and without Seizures For discussion of the c.37T-G transversion (c.37T-G, NM_201263.2) in the WARS2 gene, resulting in a trp13-to-gly (W13G) substitution, that was found in compound heterozygous state in 2 sisters with mitochondrial neurodevelopmental disorder with abnormal movements and lactic acidosis and without seizures (NEMMLAS; 617710) by Musante et al. (2017), see 604733.0001. Childhood-Onset Parkinsonism-Dystonia 3 In a 17-year-old boy with childhood-onset parkinsonism-dystonia-3 (PKDYS3; 619738), Burke et al. (2018) identified compound heterozygous missense mutations in the WARS2 gene: a W13G substitution in exon 1, affecting the mitochondrial localization signal, and a c.683C-G transversion in exon 6, resulting in a ser228-to-trp (S228W; 604733.0008) substitution in the tryptophan-tRNA ligase domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. W13G was present in the ExAC database with an allelic frequency of 0.0034 and was not predicted to be extremely deleterious, whereas S228W was not present in ExAC. Western blot analysis of patient cells showed a marked decrease in steady-state levels of WARS2 compared to controls. Patient skeletal muscle biopsy showed mild mitochondrial abnormalities, although OXPHOS activity was normal; the authors postulated that mitochondrial dysfunction contributed to nigrostriatal degeneration. The patient had onset of levodopa-responsive parkinsonism at about 2 years of age; the disorder was progressive. In a 31-year-old man with PKDYS3, Hubers et al. (2019) identified compound heterozygous missense mutations in the WARS2 gene: W13G and a c.149G-A transition, resulting in a gly50-to-asp (G50D; 604733.0009) substitution. The mutations, which were found by trio-based exome sequencing, segregated with the disorder in the family. W13G was found 9 times in the homozygous state in the gnomAD database, consistent with it being a hypomorphic allele and only disease-causing when combined with a more deleterious allele. G50D was not present in gnomAD. Functional studies of the variants and studies of patient cells were not performed. The patient developed a severe hyperkinetic movement disorder in the first years of life; he also had cognitive defects and could communicate nonverbally on a basic level. Brain imaging showed cerebellar atrophy. He did not have seizures, which may have explained his long survival. In 6 patients from 4 unrelated families with PKDYS3, Skorvanek et al. (2022) identified compound heterozygous mutations in the WARS2 gene. All patients carried a W13G variant on 1 allele. Two sibs from family 1 had a deletion of exon 2 on the other allele (604733.0011). Fibroblasts derived from these patients showed decreased levels of full-length WARS2 protein compared to controls. Two sibs from family 2 carried leu100del (604733.0004) on the other allele; functional studies were not performed. The patient from family 3 carried G50D (604733.0009) on the other allele; functional studies were not performed. The patient from family 4 carried a c.622G-T transversion, resulting in a glu208-to-ter (E208X; 604733.0012) substitution on the other allele; functional studies were not performed, but it was predicted to result in premature termination. (less)

Vertical supranuclear gaze palsy (present) , Dysarthria (present) , Parkinsonian disorder (present) , Abnormal cerebellum morphology (present) , Dystonic disorder (present) , Gait ataxia (present) , Abnormal speech pattern (present) (less)