We report a patient with biallelic variants in KIAA0586, causing JBTS23. The maternal KIAA0586 variant, c.428delG, known as rs534542684, is reported with minor allele frequency (MAF) 0.003 in the Exome Aggregate Consortium (ExAC) and in the Genome Aggregation database (gnomAD). Surprisingly, this variant has been identified in homozygosity in two healthy individuals in the European population in gnomAD and in one healthy homozygous female. In this female the KIAA0586 c.428delG transcript was shown to elude the nonsense-mediated decay (NMD) mechanism . It was suggested that the allele carrying rs534542684 could function as a hypomorphic allele, possibly by the use of an alternative start codon downstream of the variant . It is interesting to note that c.428delG is the most frequently identified variant in JBTS23, usually present in compound heterozygosity, less often in homozygosity [5, 13]. In our patient the second allele harbored a deletion removing exons 8–10.
Patients with JBTS23 present with neonatal breathing pattern anomalies, global developmental delay, intellectual disability, and brain malformations, including the molar tooth sign. In addition to the typical JBTS23 presentation, our patient manifested with Duane anomaly, previously reported only in one case . Interestingly, the patient suffered from epilepsy and had an ectopic neurohypophysis. The last feature has never been reported in patients with JBTS23.
Epilepsy is reported only in patients with mutations in five of the known JBTS causing genes: CC2D2A causing JBTS9 (OMIM# 612285), KIF7 causing JBTS12 (OMIM# 200990), KIAA0586 causing JBTS23 (OMIM# 616490), ARMC9 causing JBTS30 (OMIM# 617622), and B9D2 causing (OMIM# 614175). None of the animal models targeting KIAA0586 orthologues so far reported manifested epilepsy . Among the 42 JBTS23 patients so far reported [4, 5, 7, 11,12,13], only two suffered from epilepsy [7, 11], and SUDEP has not been reported. However, the patient presented several clinical risk factors for the occurrence of SUDEP, such as being a male with a history of seizures from a young age, often nocturnal GTCS, borderline intellectual disability, and living alone not complying to the treatment . In particular, the combination of frequent nocturnal GTCS and sleeping alone was showed to dramatically increase the risk of SUDEP . In general mortality in JBTS has not been related to epilepsy, but rather to renal or respiratory failure , however the recent management recommendations for patients with JBTS specifically mention seizures .
Our patient is the first to be reported with deleterious variants in KIAA0586 and ectopic neurohypophysis. The ectopic neurohypophysis is a midline brain malformation consisting of an aberrant pituitary development with an ectopically located posterior pituitary gland. This brain malformation can be associated with endocrinological defects ranging from isolated growth hormone deficiency to multiple anterior pituitary hormone deficiencies, but posterior pituitary function remains unchanged. However, our patient had a normal endocrinological profile. It was proposed that the occurrence of the ectopic neurohypophysis in ciliopathies might be caused by the role of the cilia in influencing pituitary development through SHH and Wnt signaling pathways .
In conclusion, we identified compound heterozygous variants in KIAA0586 in a patient with JBTS23, presenting with ectopic neurohypophysis and juvenile onset of epilepsy, which was difficult to treat and resulted in SUDEP. We expand the phenotype of JBTS23 since these features have not previously been reported in this disease. Although we report a single patient, we suggest that the onset of epilepsy in patients with JBTS23 should be promptly evaluated and treated, and deserve close monitoring, to reduce the risk of an adverse outcome. Our results highlight the value of WGS when combining different pipelines of analysis to detect SNVs/indels and larger structural variants below the resolution of diagnostic microarrays.