de novo interstitial deletions at the 11q23.3-q24.2 region

Background Jacobsen syndrome (JBS) is a contiguous gene deletion syndrome involving 11q terminal deletion. Interstitial deletions at distal 11q are rare and their contributions to the clinical phenotype of JBS are unknown. Case presentation We presented the chromosome microarray (CMA) data and the clinical features of two individuals carrying a non-overlapping de novo deletion each at the 11q23.3-q24.2 region in an effort to analyze the correlation between region of deletion at 11q and phenotype. Both deletions are likely pathogenic for patient’s condition. The deletion at 11q23.3q24.1 is associated with short stature, relative microcephaly, failure to thrive, hypotonia and sleeping disorder. The deletion at 11q24.2 involves HEPACAM and our patient’s clinical presentation (relative macrocephaly, abnormal MRI, mild developmental delay and seizure) is not inconsistent with Megalencephalic leukoencephalopathy with subcortical cysts 2B. Conclusions Our finds support the notion that more than one critical region at 11q23.3-qter are responsible for the variable clinical presentation of JBS, thus JBS is a true contiguous gene deletion syndrome where multiple loci contributed to the clinical characteristics of JBS. Small interstitial deletions at 11q23.3-q24.2 and their associated unique features also suggest emerging novel genomic disorders. Electronic supplementary material The online version of this article (doi:10.1186/s13039-016-0247-7) contains supplementary material, which is available to authorized users.

Here, we reported two individuals carrying nonoverlapping interstitial deletions at 11q23.3-q24.2 region with different degrees of DD/ID and some dysmorphic features in an effort to further define genotype-phenotype correlation.

Patient 1
Patient 1 (P1) was a 5-year-old girl born to a 29-year-old woman at 41 weeks of gestational age. Pregnancy and delivery were uneventful. Her birth weight was 2.8 kg (~15 th percentile) and birth length around 48.2 cm (~15 th percentile). She had an apparently healthy twin brother and sister. At around 5-6 months of age she was noticed to have global delay including unable to roll over, delayed crawling, sitting and standing. She was at a 5-month developmental level at the age of one. She had a history of failure to thrive and hypotonia. She came to Genetics Clinic due to dysmorphic features and global developmental delay. At 5-years of age, her height was 101 cm (−2.11 SD), weight 14 kg (−2.58 SD) and head circumference 48.3 cm (7th percentile). She had overlapping toes, dysmorphic features including mild hypertelorism (inner canthal distance 27 mm, +1SD), prominent forehead, flat facial profile, broad nose, smooth philtrum with thin upper lip, upslanting palpebral fissures with epicanthal folds. Her brain MRI was normal. No other defect was noticed.
She had a history of sleeping disorder. Notably, her parents reported that she would vocalize around bedtime, often it is associated with body rocking and head banging. She would wake up and bang her head at midnight. She would sit Indian style on her bed and leaned forward until she banged her head on the mattress. This occurred in a fairly fast and rhythmic pattern. Often she would moan during such a movement and many times the moan escalated into very loud scream. She also had the rocking behavior during the daytime that she would move her back up against a hard surface and then rocked her lower back and buttocks on the floor. She was diagnosed as jactatio capitis nocturna and such behavior had improved but not resolved entirely.

Patient 2
Patient 2 (P2) was a boy who came to hospital due to fever, mild developmental delay and seizure at the age of 10 months. He was a full term second child to a healthy parent who had a healthy 4-year-elder daughter. He was delivered via cesarean section without complication during pregnancy or delivery. His birth weight was 3.25 kg (25-50th percentile) and birth length was 50 cm (25-50th percentile). He had no significant medical history prior to presentation. No family history of seizure, autism, mental retardation or other neurologic impairments. He raised his head around 3-4 months of age, rolled over around 6-7 months of age, and pronounced first word at about 10 months of age. His developmental quotient (DQ) and the mental index (MI) suggested that he had mild development delay by the Denver Development Screening Test score (DQ = 51 and MI = 63). At the age of 10 months, his weight was 9.4 kg (30th percentile) and height 72.5 cm (25th percentile). He presented with a relative macrocephaly (circumference was 47.5 cm (+1.3SD)), mild hypertelorism, low nasal bridge, thin upper lip and strabismus. The magnetic resonance imaging (MRI) revealed the widening of the frontotemporal lobe, full bilateral ventricles and deep parietal sulci. He had normal electroencephalogram and electromyography. He was diagnosed with acute pharyngitis, secondary seizure, psychomotor retardation and mild development delay as well as cerebral hypogenesis.

Method
Chromosomal microarray (CMA) analyses DNA sample was extracted from peripheral blood lymphocytes using standard protocol, microarray was performed using Agilent 244 K array for patient 1 and the illumina HumanSNP cyto-12 array for patient 2.

Discussion
Interstitial deletions on 11q are rare and the genotypephenotype study had been hindered by the small number of cases reported and a lack of sufficient details about patient's clinical phenotype. So far there are only 11 interstitial deletion cases at the 11q23.3-q25 region have been reported (Additional file 1:  [14]. Two patients reported here added to this list. P1 presented with short stature, DD/ID, relative microcephaly, sleeping disorder, some dysmorphic features and P2 exhibited mild DD/ID, relative macrocephaly, mild hypertelorism. A summary of the clinical features of the eight previously reported patients with 11q23-qter interstitial deletions and two present cases is listed in Table 1. The prevalence of phenotype among these interstitial deletion patients can not be quantified for the small number, but the summarization collectively support the notion that Jacobsen syndrome is a contiguous gene deletion syndrome where multiple genes (regions) involved within the deletion region play roles to the syndromic phenotypes.
DD/ID is a consistent feature of JBS. It is also a common feature of patients with 11q interstitial deletions (Table 1). Taoyun Ji et al. proposed a critical region for DD/ID near the telomere defined by a 4.1 Mb deletion (case 3 in Fig. 2) [5]. The deletion detected in our P2 is the smallest in size, it overlaps with deletions detected in case 1 [13] and 4 [11]. All three cases had the clinical presentation of DD/ ID, based on this observation, we propose a novel DD/ID locus at 11q24.2 (chr11:124635144-125390604). Similarly, the deletion detected in our P1 may define another novel DD/ID locus at 11q23.3-q24.1 (chr11: 120410050-122085906). Thus there are multiple loci on 11q that the haploinsufficiency of each region is likely associated with DD/ID.
It is interesting to note that patient 1 exhibited the characteristic features of jactatio capitis nocturna, also known as rhythmic movement disorder (RMD). Most of RMD will spontaneously resolve by 4 years of age [15]. Our patient's condition had improved but not resolved entirely at age 5. The underlying cause of RMD is currently unknown, the deletion in P1 may provide a clue for investigating the molecular mechanism of RMD. 13 RefSeq genes including 10 OMIM genes (GRIK4, LRRC35, TECTA, SC5DL, SORL1, MIR100HG, MIR125B1, BLID, MIRLET7A2 and MIR100) are involved in the deletion. But it is unclear which gene or genes are likely responsible for the sleeping disorder. GRIK4 (OMIM #600282) encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. Takenouchi T et al. and Pickard BS et al. suggested that the haploinsufficiency of GRIK4 was related to DD, mental retardation, schizophrenia and bipolar disorder [16,17]. The developmental delay present in our patient may be explained by the GRIK4 deletion.
The deletion interval in P2 encompassed 6 OMIM genes (ROBO3, ROBO4, HEPACAM, HEPN1, PKNOX2 and FEZ1). Sequence variants in HEPACAM (OMIM  [18][19][20]. The clinical presentation of the autosomal form is milder, some features improve with age. Recently haploinsufficiency of HEPACAM was considered as a cause of two patients with heterozygous deletion at 11q23.3q24.2 interstitial deletion 11q24 and clinical features of MLC [14]. P2 was presented with relative macrocephaly, abnormal MRI mild developmental delay and seizure, which is not inconsistent with MLC2B. The much smaller deletion detected in P2 overlap with the interstitial deletion in patient 2 of Yamamoto's report. The smallest overlapping region between this two cases can exclude the involvement of FEZ1 (OMIM #604825) gene which plays a role in axonal outgrowth and has been proposed as a candidate gene for abnormal MRI by Tyson et al. [11].