Background: A 17-year-old girl presented with syndromic cerebral palsy, intellectual disability, dysmorphic features and muscular hypotonia. At birth via C-section due to breech position, the girl was severely hypotonic and had low set ears, a short philtrum, a tented mouth, retromicrognathia, a cleft of the posterior palate, and bilateral club feet. She developed postnatal microcephaly and scoliosis and shows major hypotonia with areflexia in upper and lower extremities, spasticity, and contractures in the legs. She was able to sit alone at age 6 and used first words at age 8. While tube feeding was needed for multiple years, she recently started to eat solid foods . A muscular biopsy at age 4 showed unspecified myopathy with an excess of type 1 fibres and atrophy of type 2 fibres. There was no indication of muscular dystrophy or mitochondrial myopathy. CPK values, brain MRI, and EMG were normal. Earlier genetic testing, including microarray, chromosome 15 methylation analysis, screening for congenital myotonic dystrophy, and analyses of mtDNA on muscular tissue, showed no abnormalities. Results: We report a novel, maternally inherited, likely pathogenic heterozygous variant in the KCNK9 gene: GRCh37 (hg19): NM_001282534.2: c.710C>T; p.(Ala237Val), detected by gene panel testing for neurodevelopmental disorders (Illumina). Discussion: KCNK9 is a paternally imprinted gene on chromosome 8 that encodes the potassium channel subunit TASK3, that forms dimers to shape two-pore domain potassium leak channels. Pathogenic changes on the maternally inherited allele result in Birk-Barel or KCNK9 imprinting syndrome (OMIM #612292), characterized by congenital central hypotonia resulting in feeding difficulties, global developmental delay, and dysmorphic features. Almost all patients described today carry one of two missense variants (GRCh37 (hg19): NM_001282534.2: c.706G>C and c.706G>A), both of which lead to the same amino acid change (p.Gly236Arg), which was shown to reduce the functional currents of the TASK3 channel by 80%. In 2019, an additional patient was described, carrying an amino acid substitution at the next amino acid position: GRCh37 (hg19): NM_001282534.2: c.710C>A, p.(Ala237Asp). The novel variant in our patient involves a different amino acid substitution at the same position as the variant in the patient of Šedivá et al. (p.(Ala237Val)), adding strength to the interpretation of both variants as likely pathogenic. Although no functional studies were performed in either patient with a substitution at p.Ala237, the clear phenotype of both patients also supports causality of the detected variants. In addition, both patients show selective atrophy of type II fibres and hypertrophy of type I fibres on muscle biopsy, which may be compatible with neurogenic changes similar to what is seen in spinal muscular atrophy (SMA). From the original group of patients described by Barel et al. (2008), two patients showed signs of SMA on muscle biopsy. Conclusion: Our patient shows the typical clinical phenotype of Birk-Barel syndrome, likely caused by the novel, maternally inherited KCNK9 variant c.710C>T; p.(Ala237Val). This case provides further support that Birk-Barel syndrome is caused by substitutions leading to changes at both positions p.Gly236 and p.Ala237 of the TASK3 channel.
|Publication status||Published - 17 Sep 2021|
|Event||21st Annual Meeting of the Belgium Society for Human Genetics: Reproductive Genetics - Crowne Plaza Brussels Airport, Diegem, Belgium|
Duration: 17 Sep 2021 → 17 Sep 2021
|Conference||21st Annual Meeting of the Belgium Society for Human Genetics|
|Period||17/09/21 → 17/09/21|