UNASSIGNED: Birk-Barel syndrome, also known as KCNK9 imprinting syndrome, is a rare fertility disorder. And the main clinical manifestations include congenital hypotonic, craniofacial malformation, developmental delay, and intellectual disability. Generally, such patients could be diagnosed beyond the infant period. Moreover, the delayed diagnosis might lead to a poor prognosis of rehabilitation therapy. However, neonatal obstructive sleep apnea (OSA) was seldom reported in Birk-Barel syndrome. Here, we reported a severe neonatal OSA case induced by Birk-Barel syndrome, resulting in an early diagnosis with improved outcomes by integrative management.
UNASSIGNED: The proband was a neonate presenting with recurrent severe OSA, with craniofacial deformity and congenital muscle hypotonia. Bronchoscopy examinations indicated a negative finding of pharyngeal and bronchus stenosis, while laryngomalacia had been observed. Whole exon sequencing demonstrated a c. 710C>A heterozygous variant resulting in a change of amino acid (p.A237D). This variant resulted in a change of amino acid sequence, affected protein features and changed splice site leading to a structural deformation in KCNK9 protein. This p.A237D variant also affected the crystal structure on the p.G129 site. Additionally, we used the mSCM tool to measure the free energy changes between wild-type and mutant protein, which indicated highly destabilizing (-2.622 kcal/mol).
UNASSIGNED: This case report expands the understanding of Birk-Barel syndrome and indicates that OSA could serve as the on-set manifestation of Birk-Barel syndrome. This case emphasized genetic variants which were associated with severe neonatal OSA. Adequate WES assessment promotes early intervention and improves the prognosis of neurological disorders in young children.

Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, KCNK9 gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that KCNK9 is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of KCNK9, occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). KCNK9 hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the KCNK9 gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the KCNK9 DMR predicts for increased TASK3 expression and mitochondrial membrane potential (p < 0.001). This is the first identification of the KCNK9 DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the KCNK9 DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the KNCK9 DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.

Birk-Barel syndrome, alternatively known as KCNK9 imprinting syndrome, is caused by a missense mutation in the potassium two pore domain channel subfamily K member 9 (KCNK9) gene on chromosome 8q24.3. This syndrome demonstrates dominant inheritance and is imprinted with paternal silencing, where the paternally inherited allele is silenced, and the maternally inherited allele is active. Congenital hypotonia, palatal abnormalities, intellectual disability, severe feeding difficulties, and dysmorphic facial features characterize this sporadic genetic syndrome. To date, there are approximately 21 molecularly diagnosed individuals worldwide described in the literature. We describe the first known case of Puerto Rican ethnicity, a 16-month-old female born prematurely at 36-weeks with Birk-Barel syndrome, confirmed with whole-exome sequencing, and her response to non-invasive ventilation as a treatment for her sleep breathing disorder.

Ring chromosome 8 (r(8)) is one of the least frequent ring chromosomes. Usually, maternal chromosome 8 forms a ring, which can be lost from cells due to mitotic instability. The 8q24 region contains the imprinted KCNK9 gene, which is expressed from the maternal allele. Heterozygous KCNK9 mutations are associated with the imprinting disorder Birk-Barel syndrome. Here, we report a 2.5-year-old boy with developmental delay, microcephaly, dysmorphic features, diffuse muscle hypotonia, feeding problems, motor alalia and noncoarse neurogenic type of disturbance of muscle electrogenesis, partially overlapping with Birk-Barel syndrome phenotype. Cytogenetic analysis of lymphocytes revealed his karyotype to be 46,XY,r(8)(p23q24.3)[27]/45,XY,-8[3]. A de novo 7.9 Mb terminal 8p23.3p23.1 deletion, a 27.1 Mb 8p23.1p11.22 duplication, and a 4.4 Mb intact segment with a normal copy number located between them, as well as a 154-kb maternal LINGO2 gene deletion (9p21.2) with unknown clinical significance were identified by aCGH + SNP array. These aberrations were confirmed by real-time PCR. According to FISH analysis, the 8p23.1-p11.22 duplication was inverted. The ring chromosome originated from maternal chromosome 8. Targeted massive parallel sequencing did not reveal the KCNK9 mutations associated with Birk-Barel syndrome. Our data allow to assume that autosomal monosomy with inactive allele of imprinted gene arising from the loss of a ring chromosome in some somatic cells may be an etiological mechanism of mosaic imprinting disorders, presumably with less severe phenotype.

Sensing of hypoxia and acidosis in arterial chemoreceptors is thought to be mediated through the inhibition of TASK and possibly other (e.g., BKCa ) potassium channels which leads to membrane depolarization, voltage-gated Ca-entry, and neurosecretion. Here, we investigate the effects of pharmacological inhibitors on TASK channel activity and [Ca2+ ]i -signaling in isolated neonatal rat type-1 cells. PK-THPP inhibited TASK channel activity in cell attached patches by up to 90% (at 400 nmol/L). A1899 inhibited TASK channel activity by 35% at 400 nmol/L. PK-THPP, A1899 and Ml 365 all evoked a rapid increase in type-1 cell [Ca2+ ]i . These [Ca2+ ]i responses were abolished in Ca2+ -free solution and greatly attenuated by Ni2+ (2 mM) suggesting that depolarization and voltage-gated Ca2+ -entry mediated the rise in [Ca2+ ]i. Doxapram (50 μmol/L), a respiratory stimulant, also inhibited type-1 cell TASK channel activity and increased [Ca2+ ]i. . We also tested the effects of combined inhibition of BKCa and TASK channels. TEA (5 mmol/L) slightly increased [Ca2+ ]i in the presence of PK-THPP and A1899. Paxilline (300 nM) and iberiotoxin (50 nmol/L) also slightly increased [Ca2+ ]i in the presence of A1899 but not in the presence of PK-THPP. In general [Ca2+ ]i responses to TASK inhibitors, alone or in combination with BKCa inhibitors, were smaller than the [Ca2+ ]i responses evoked by hypoxia. These data confirm that TASK channel inhibition is capable of evoking membrane depolarization and robust voltage-gated Ca2+ -entry but suggest that this, even with concomitant inhibition of BKCa channels, may be insufficient to account fully for the [Ca2+ ]i -response to hypoxia.

Patients with KCNK9 imprinting syndrome demonstrate congenital hypotonia, variable cleft palate, normal MRIs and EEGs, delayed development, and feeding problems. Associated facial dysmorphic features include dolichocephaly with bitemporal narrowing, short philtrum, tented upper lip, palatal abnormalities, and small mandible. This disorder maps to chromosomal region 8q24, and it is caused by a specific missense mutation 770G>A in exon 2, replacing glycine at position 236 by arginine (G236R) in the maternal copy of KCNK9 within this locus. KCNK9 (also called TASK3) encodes a member of the two pore- domain potassium channel (K2P) subfamily. This gene is normally imprinted with paternal silencing, thus a mutation in the maternal copy of the gene will result in disease, whereas a mutation in the paternal copy will have no effect. Exome sequencing in four new patients with developmental delay and central hypotonia revealed de novo G236R mutations. Older members of a previously reported Arab-Israeli family have intellectual disability of variable severity, persistent feeding difficulties in infancy with dysphagia of liquids and dysphonia with a muffled voice in early adulthood, generalized hypotonia, weakness of proximal muscles, elongated face with narrow bitemporal diameter, and reduced facial movements. We describe the clinical features in four recently recognized younger patients and compare them with those found in members of the originally reported Arab-Israeli family and suggest this may be a treatable disorder. © 2016 Wiley Periodicals, Inc.

The phenotype overlap between autism spectrum disorders (ASD) & intellectual disabilities (ID) is mirrored at the genetic level, with common genes being reported mutated in variety of developmental disabilities. However despite widespread genetic screening for mutations, in approximately 40-60% of childhood developmental disorders the genetic cause remains unknown. Several genome-wide linkage screens in ASD have identified a locus mapping to distal 8q. We have recently identified a novel brain-specific imprinted cluster at this location, which contains the reciprocally expressed maternal KCNK9 and paternally expressed non-coding PEG13 transcripts, the latter located within an intron of TRAPPC9. Interestingly, mutations of KCNK9 and TRAPPC9 have been reported in Birk-Barel mental retardation and non-syndromic familial forms of ID, respectively. Here, we report a genetic screen for KCNK9 coding mutations and potential epigenetic aberrations that could result in deregulated imprinting in a cohort of 120 ID, 86 ASD and 86 Tourette syndrome patients. Fifteen of the ID patients had clinical characteristics overlapping with Birk-Barel syndrome. Sequencing of the two coding exons of KCNK9 failed to identify pathologic mutations, with only one variant, rs2615374, being present with allele frequencies similar to those described in dbSNP database. DNA methylation profiling of the KCNK9 and TRAPPC9 promoters, the maternally methylated PEG13 DMR and a long-range enhancer region were normal in all patients. Our findings suggest that mutations of KCNK9 or epigenetic disturbances within the PEG13 imprinted cluster do not significantly contribute to the cause of the developmental disabilities tested in this study.