Rare case of a heterozygous microdeletion 9q21.11-q21.2: Clinical and genetic characteristics

Copy number variants (CNVs) are a significant cause leading to neurodevelopmental disorders such as intellectual disability, epilepsy, autism spectrum disorders and developmental delay. Up to 3.0-4.0% of the general population is affected by intellectual disability, which makes it one of the most common neurological disorders [1]. Intellectual disability has been observed in patients carrying chromosomal aberrations or gene mutations.

Boudry-Labis et al. [2] proposed a novel microdeletion syndrome, involving a deletion at 9q21.13 and presenting with intellectual disability, speech delay, epilepsy, and characteristic facial features. They have reported 13 patients [2]. The range of the deletion spanned from 2.2 to 12.6 Mb and included a different number of genes. Here, we report a girl with mild intellectual disability, speech delay and mild facial dysmorphism with 9q21.11-q21.2 microdeletion of about 9655 Mb in size.

The proband is a 10-year-old girl. She was referred to us for genetic consultation because of mild intellectual disability, speech delay and mild facial dysmorphism.

She was born full-term to non consanguineous healthy parents after an uneventful pregnancy with no evidence of asphyxia. At birth, weight, length, and head circumference were normal. There was no relevant family history. She had a history of global developmental delay in infancy. She walked at the age of 2 years. She said her first words at 18 months of age and her first short sentence at the age of 2 years. At the age of 6 she was admitted to the hospital to establish a diagnosis regarding her developmental delay and short stature. She attends a mainstream school with teacher aide support.

On examination, her height was 135 cm, weight 29 kg and head circumference 53.2 cm. She had an elongated face with a prominent chin, broad forehead, arched bushy eyebrows and long eyelashes. She had hypertelorism and the palpebral fissures were down-slanting. Her nose had a broad prominent root. Her palate was narrow and highly arched. She had a thin upper lip, long philtrum, dystrophic teeth and excessive salivation. She had pes planus with large feet and short toes (Figure 1). After a walk of kilometer and a half she complained of cramp (pain) in her calves. A consultation with a child psychologist showed a mild intellectual disability (IQ ~55, Wechsler Intelligence Scale for Children was used), cognitive deficits in attention with reduced volume, stability and concentration. Memory: difficulty in remembering and reproducing information. Thinking: clearly, figuratively. Cranial computed tomography (CT) scans and ultrasound of internal organs were performed and were normal.

Cytogenetic analysis was performed on cultured lymphocytes and skin fibroblasts by G-banding according to standard procedures. The SNP-array karyotyping was performed using microarray Illumina Human CytoSNP-12 (Illumina Inc., San Diego, CA, USA). The microchip contains a total of number of 301,232 SNP variants representative of the entire human genome. Genomic positions refer to the Human Genome February 2009 assembly (GRCh37/hg19).

Cytogenetic analysis revealed a low-level mosaicism in blood and skin of the girl with a cell line carrying a small additional marker ring chromosome: mos47,XX,+mar[4]/46,XX[96] (lymphocytes) and mos47,XX,+mar[16]/46,XX [84] (skin fibroblasts). The mother had a normal karyotype. Chromosomal analyses of the father could not be carried out due to his lack of consent. (Figure 2).

Figure 1

Figure 2

For further characterization of the found marker chromosomes we applied SNP-array of genomic DNA from buccal swab, which showed a heterozygous partial deletion of the long arm of the chromosome 9 with size of about 9655 Mb. The deletion encompasses 43 human genes (Figure 3). To clarify the origin of the marker chromosome we offered fluorescent in situ hybridization (FISH) analysis, but the mother refused.

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.

Figure 3

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. Thirty-one (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.