ClinVar Genomic variation as it relates to human health

Seizures (present) , Infantile muscular hypotonia (present) , Impaired pain sensation (present) , Hypophosphatemia (present) , Global developmental delay (present) , Chorea (present) , Brain atrophy (present) (less)

Gastroesophageal reflux (present) , West syndrome (present) , Brachycephaly (present) , Micrognathia (present) , Cortical atrophy (present) , Seizures (present) , Psychomotor retardation (present) , Hypotonia (present) , Visual impairment (present) (less)

In a 10-year-old girl with developmental and epileptic encephalopathy-36 (DEE36; 300884), de Ligt et al. (2012) identified a de novo heterozygous c.320A-G transition in the ALG13 gene, resulting in an asn107-to-ser (N107S) substitution. The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. The patient also carried a de novo heterozygous E89K variant in the KRT32 gene (602760) that was not thought to be pathogenic. The patient was born at 34 weeks' gestation and showed neonatal feeding problems, hypotonia, seizures, and severely delayed psychomotor development. She had a large head circumference (greater than 2.5 SD), and brain MRI showed hydrocephalus, myelination delay, and wide sulci. Other features included self-mutilation, sleep disturbance, and dysmorphic features, such as hypertelorism, broad coarse face, low-set ears, mild retromicrognathia, small hands and feet, joint contractures, and scoliosis. Isoelectric focusing of serum transferrin was not performed. The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous N107S mutation in 2 unrelated girls (trios ij and dg) with early-onset epileptic encephalopathy. The patients were part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. The patients had onset of seizures at ages 1 and 4 months, respectively. EEG showed hypsarrhythmia. Both showed severely delayed psychomotor development after the onset of seizures. A statistical likelihood analysis indicated that the probability of this finding occurring by chance was p = 7.8 x 10(-12). Functional studies were not performed. Michaud et al. (2014) identified a de novo heterozygous N107S mutation (c.320A-G, NM_001099922.2) in the ALG13 gene in a girl with DEE36. The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed. The girl also had a heterozygous 9p24.2 deletion inherited from her unaffected mother that was predicted to be benign. Smith-Packard et al. (2015) reported a 7-year-old girl with DEE36 who carried a de novo heterozygous N107S mutation identified by whole-genome sequencing. The patient had normal glycosylation of serum transferrin. Functional studies of the variant and studies of patient cells were not performed; however, the authors noted that the mutation occurs at a highly conserved residue within a loop deep inside the protein in a presumed functional domain, and thus may impact the catalytic activity. She presented at 8 months of age with infantile spasms associated with hypsarrhythmia on EEG. She had severe cognitive impairment with limited speech. Dimassi et al. (2016) identified a de novo heterozygous N107S mutation in a 6-year-old girl with DEE36. The mutation was found by whole-exome sequencing of 10 parent-child trios. The patient had normal glycosylation of serum transferrin. The mutation was not reported in the ExAC database; functional studies of the variant were not performed. At 2 months of age, the patient developed infantile spasms associated with hypsarrhythmia on EEG and thereafter showed severely delayed psychomotor development with inability to sit and limited eye contact. Ng et al. (2020) identified a de novo heterozygous N107S mutation in the ALG13 gene in 23 patients who underwent next-generation sequencing. Clinical details were consistent with DEE36 and a diagnosis of early-onset seizures with West syndrome. All but 1 were female: the 1 male patient with the mutation (CDG-0083) had a phenotype consistent with DEE36. Ng et al. (2020) noted that the N107S variant is not present in the gnomAD database. In vitro studies in alg13-null yeast showed that the N107S variant could restore a growth defect, but was unable to restore abnormal glycosylation of carboxypeptidase Y (CPY). The findings suggested that these mutations affect alg13 function in yeast. None of the patients tested showed evidence of a glycosylation defect, although 1 patient (CDG-1017) had mild and transient abnormalities that later resolved to normal. The patients had onset of infantile spasms at a mean age of 6.5 months; most had hypsarrhythmia on EEG, consistent with West syndrome. All had global developmental delay with impaired intellectual development. In a 2-year-old Emirati girl with DEE36, Hamici et al. (2017) identified heterozygosity for the N107S mutation in the ALG13 gene. The de novo mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. X-chromosome inactivation studies in the patient's leukocytes showed a random pattern of X-chromosome inactivation. The patient had severe infantile epileptic encephalopathy. In a 3.5-month-old boy with DEE36, Galama et al. (2018) identified heterozygosity for the N107S mutation in the ALG13 gene. The de novo mutation was identified by whole-exome sequencing. This patient was the first male with DEE36 to be identified with the N107S mutation in the ALG13 gene. (less)