Balkan Journal of Medical Genetics

RARE CASE OF A HETEROZYGOUS MICRODELETION 9q21.11-q21.2: CLINICAL AND GENETIC CHARACTERISTICS
Ivanov HY, Stoyanova V, Ivanov I, Linev A, Vazharova R, Ivanov S, Balabanski L, Toncheva D
*Corresponding Author: Dr. Hristo Y. Ivanov, Department of Pediatrics and Medical Genetics, Medical University Plovdiv, Vasil Aprilov 15-A Str., Plovdiv 4002, Bulgaria. Tel: +359-884-827-070. Fax: +359-326-022-338. E-mail: doctorhristoivanov@yahoo.com
page: 59

DISCUSSION

Here, we report a girl with a 9655 Mb de novo deletion at 9q21.11-q21.2 presenting with mild intellectual disability, speech delay and characteristic facial features. Review of the literature showed that only 13 patients with a micro-deletion 9q21 have been reported [2,3]. The clinical symptoms observed in our patient are similar to those seen in the other patients with a deletion at 9q21.11-q21.2. In the cases described by Boudry-Labis et al. [2], they found mental retardation and speech delay in all patients, autistic behaviour, epilepsy and mild facial dysmorphism including hypertelorism, feature-less philtrum, thin upper lip, and in three cases, hypertrichosis. Our patient showed some of the phenotypic features of the cases described by Boudry-Labis et al. [2] but not all of them. She presented with mental retardation, speech delay, mild facial dysmorphism with hypertelorism, feature-less philtrum and thin upper lip but no epilepsy and autistic behavior. Mosaicism in association with ring chromosomes is a well-known fact. Liehr et al. (4) summarized 144 cases, 78 of which (54.0%) showed mosaic karyotypes. Thirtyone (out of 78) of the cases had no abnormal clinical findings. The non mosaic cases showed an even lower rate of abnormal clinical findings, in only 27 of 66 cases clinical abnormalities were described [4]. It is very difficult to interpret the influence of the market chromosome to the phenotype. Small marker ring chromosomes can be formed in association with a deletion of a part of the chromosome [4]. Due to the low-level mosaicism, molecular karyotyping could not identify the origin of the marker chromosome. Thus, the contribution of the marker chromosome to the phenotype remains unknown. Four genes (RORβ, PRUNE2, PCSK5 and TRPM6) located in the deleted segment are associated with a neurological phenotype, especially intellectual disability. From these, only TRPM6 is associated with a known human disorder (OMIM 602014). The other genes are not expressed in the brain and do not appear to be suitable candidates for neurodevelopmental disorders [2]. The RORβ gene is expressed only in certain regions of the brain: the cerebral cortex, the thalamus, the hypothalamus, the pineal gland and the retina [5,6]. RORβ null mice present with behavioral changes such as reduced anxiety behavior and several motor defects like lack of some neurological reflexes and abnormal gait. Some recent studies have established a strong genetic link between RORβ and bipolar disorder [9] and the measure of verbal intelligence [10]. The PRUNE2 gene has involvement in neuronal apoptosis and is expressed in neurons in the brain, cerebellum, retina and spinal cord [11]. Recent studies suggested this gene as candidate gene to susceptibility to Alzheimer’s disease and intellectual disability [11]. The PCSK5 gene is involved in transmitting of the nerve signals and is highly expressed in the nervous system, especially in the spinal cord and in the pineal gland. A recent study reported that zebra fish embryos lacking the coorthologue of the PCSK5 gene, PC5.1, have abnormal deposition of the neuromast within the lateral line system and have an abnormal touch response. This is consistent with the knowledge that the lateral line plays a role in the sensing the environment and in spatial awareness [12]. Mutations in the TRPM6 gene are associated with hypomagnesemia with secondary hypocalcemia (OMIM 602014). These patients presented with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany, which can explain our patient’s complaint of pain in the calves. In agreement with Boudry-Labis et al. [2], we could speculate that among the genes of the interstitial deletion at 9q21.11-q21.2, RORβ, PRUNE2, PCSK5 and TRPM6 could best explain the phenotype of our patient, characterized by mild intellectual disability and characteristic facial features. In conclusion we can say that this case illustrates the need to implement high resolution methods in patients with intellectual disability and mild dysmorphism. Moreover, the genes associated with intellectual disability may warrant further investigation.

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