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.

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.

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.