Introduction: The pure interstitial trisomy 11q11q23.2 is an uncommon genomic disorder associated with nonrecurrent intrachromosomal duplications. The phenotype is characterized by intellectual disability and craniofacial abnormalities. Given their uncommonness, a comprehensive genotype-phenotype correlation has not fully been defined. Case Presentation: We report the clinical and cytogenomic characterization of a 5-year-old boy with intellectual disability, psychomotor retardation, craniofacial dysmorphism, genital anomalies, and pure interstitial trisomy 11q arising from a nonrecurrent 11q13.1q22.3 intrachromosomal duplication in a high-mosaic state (>80%). The duplicated chromosome was characterized by cytogenetics, multicolor banding FISH, and SNP array. We demonstrated the wide mosaic distribution of the 11q duplication by interphase FISH in tissues from different embryonic germ layers. The duplication involves a copy number gain of 45.3 Mb containing 22 dosage-sensitive genes. We confirmed the overexpression of dosage-sensitive genes along the duplicated region using RT-qPCR. Discussion: Only 8 patients have been described. Our patient shares clinical features with previous reports but differs from them by the presence of genital anomalies. We provide a detailed clinical review and an accurate genotype-phenotype correlation and propose PC, NDUFV1, FGF3, FGF4, and DHCR7 as dosage-sensitive genes with a possible role in the clinical spectrum of our patient; however, expression changes of FGF3/4 were not detected since they must be regulated in a spatiotemporal way. This patient contributes to the accurate description of the pure interstitial trisomy 11q. Future reports could continue to delineate the description, considering the relationship between the chromosome segment and the genes involved.

Established Facts

  • The pure interstitial trisomy 11q (PIT11q) is a rarely described genomic disorder caused by nonrecurrent intrachromosomal duplications spanning from 11q11 to 11q23.2.

  • Given the uncommonness of PIT11q, a comprehensive genotype-phenotype correlation has not fully been defined.

  • The 11q11q23.2 interstitial region includes dosage-sensitive genes; however, most of them have not been specifically studied for triplo-sensitivity.

Novel Insights

  • The 11q interstitial duplication of 45.3 Mb in our patient is the largest detected duplication compared with previous reports.

  • Our patient is the second reported case of high-level mosaicism for an isolated 11q interstitial duplication and is the first in which a wide mosaic distribution is demonstrated in tissues coming from different embryonic germ layers.

  • Genital anomalies present in our patient have not been previously reported; these features contribute to the further delineation of the clinical spectrum of PIT11q.

  • We confirmed the overexpression of dosage-sensitive genes located in 11q duplicated region which could probably contribute to the pathogenicity of PIT11q.

The pure 11q trisomy is a rare entity which commonly involves the duplication of the 11q distal region, from 11q23.3 to 11q25 [Burnside et al., 2009; Chen et al., 2013; Chen et al., 2014; Choi et al., 2015]. Even more, nonrecurrent intrachromosomal duplications spanning from 11q11 to 11q23.2 are much less frequent. These patients are carriers of pure interstitial trisomy 11q (PIT11q) and manifest a quite variable phenotype; the main clinical features include moderate to mild degrees of intellectual disability, developmental delay, abnormal cranial shapes (with confirmed craniosynostosis in some cases), facial dysmorphism (including abnormal ears, frontal bossing, hypertelorism, small nose, micro-retrognathia, and short neck), dental anomalies, and minor congenital limb malformations. Additionally, major clinical findings can include brain malformations, congenital heart defects, and recurrent respiratory or ear infections [Legius et al., 1996; Yelavarthi and Zunich, 2004; Jehee et al., 2007; Zarate et al., 2007; Ziebart et al., 2013; Grillo et al., 2015; Johnson et al., 2015].

To date, only eight cases with PIT11q have been reported in the literature. Since these patients present osseous developmental malformations, it has been suggested that the increased dosage of the FGF3 and FGF4 genes is associated with this phenotypic feature [Legius et al., 1996; Jehee et al., 2007; Ziebart et al., 2013; Grillo et al., 2014]. The FGF3/4 genes are located in 11q13.3 and encode ligand mitogens, which regulate migration and proliferation of osteoblasts, and the hyperactivation of FGF receptors due to activating mutations has been found in congenital skeletal disorders [Goos and Mathijssen, 2019; Xie et al., 2020]. Possibly, the overexpression of the FGF genes may cause hyperactivation of FGF receptors in patients with PIT11q. Nevertheless, the expression levels of FGF3 and FGF4 have never been evaluated in these patients.

Given their uncommonness, a comprehensive genotype-phenotype correlation for PIT11q has not fully been defined. Additionally, according to ClinGen database, until now, none of the dosage-sensitive genes located at the interstitial region of the 11q arm have been specifically analyzed for triplo-sensitivity. However, these patients provide an opportunity to elucidate the clinical consequences of gene dosage increases [Legius et al., 1996; Yelavarthi and Zunich, 2004; Jehee et al., 2007; Zarate et al., 2007; Ziebart et al., 2013; Grillo et al., 2015; Johnson et al., 2015].

In this report, we present the cytogenomic features and clinical description of a new patient with a PIT11q arising from an intrachromosomal 11q13.1q22.3 mosaic duplication. We also evaluate the expression levels of seven dosage-sensitive genes within the duplicated region, including the FGF3 and FGF4, and include a literature review of previously reported cases with similar genetic findings to correlate the genes involved and delineate the phenotype.

The proband is a 5-year-old male with dysmorphic syndrome, intellectual disability, and severe psychomotor retardation, who was referred to the Human Genetics Department of National Pediatric Institute (Mexico City, Mexico). He was the third full-term child of healthy non-consanguineous parents. His weight was 13 kg (Z-2.6), height was 90 cm (Z-3.7), and OFC was 46 cm (Z-3.4). He presented craniofacial dysmorphism that included turricephaly, plagiocephaly, flat occiput, triangular face, and prominent forehead. He also showed hypertelorism, broad nasal bridge, ptosis, short downslanting palpebral fissures, inverse epicanthus, anteverted nostrils, asymmetric ear pavilions with absence of anti-helix, long philtrum, everted lower lip, dental malocclusion type 2, and micro-retrognathia (Fig. 1a, b). He also presented corporal asymmetry with short neck, telethelia, and umbilical hernia. He had digital anomalies such as brachydactyly and fifth finger clinodactyly (Fig. 1c) and lower extremities with genu varus and equinovarus foot (Fig. 1d). Hypoplastic genitalia with micropenis and cryptorchidism were identified (Fig. 1e). The brain MRI revealed corpus callosum dysgenesis (Fig. 1f) and no findings in the cerebellum were noted (Fig. 1g). Renal USG and routine blood test were normal.

Fig. 1.

Clinical features of the patient. a, b The patient showing craniofacial dysmorphic features including abnormal head shape, facial asymmetry with hypertelorism, broad nasal bridge, asymmetric ear pavilions, long philtrum, everted lower lip, and micro-retrognathia. c, d Abnormal limbs with brachydactyly, fifth finger clinodactyly, and equinovarus foot. e Abnormal genitalia showing micropenis and cryptorchidism. f, g MRI showing dysgenesis of corpus callosum and normal cerebellum structure (white arrows).

Fig. 1.

Clinical features of the patient. a, b The patient showing craniofacial dysmorphic features including abnormal head shape, facial asymmetry with hypertelorism, broad nasal bridge, asymmetric ear pavilions, long philtrum, everted lower lip, and micro-retrognathia. c, d Abnormal limbs with brachydactyly, fifth finger clinodactyly, and equinovarus foot. e Abnormal genitalia showing micropenis and cryptorchidism. f, g MRI showing dysgenesis of corpus callosum and normal cerebellum structure (white arrows).

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Cytogenomic Analysis

The cytogenetic analysis of the patient and his parents was performed on GTG-banded metaphases (450–700 band resolution) from blood lymphocyte cultures stimulated with phytohemagglutinin, according to standard procedures. Fifty metaphases were analyzed and interpreted based on ISCN 2020 [International Standing Committee on Human Cytogenomic Nomenclature et al., 2020]. Chromosome 11 multicolor banding fluorescence in situ hybridization was performed to obtain an accurate characterization of the intrachromosomal 11q duplication. Metaphase spreads were obtained by standard procedures, and the commercial chromosome 11-specific probe cocktail (XCyte 11 MetasystemsTM) was used following the manufacturer’s protocol. At least 10 metaphases displaying the 11q duplicated chromosome were registered. The Affymetrix CytoScan® 750k Array 46 (Santa Clara, CA) was performed according to standardized protocols provided by the manufacturer. The Affymetrix® Chromosome Analysis Suite (ChAS) 4.2 software was used to detect and analyze the chromosome copy number variations of the sample. Duplicated 11q regions were determined by the increase in the log R ratio, and mosaic proportions were measured by B allele frequencies. The chromosome positions were shown according to the GRCh37 (hg19).

Mosaic 11q Duplication Distribution in Different Tissue Samples Using Interphase FISH

We investigated the mosaic distribution of 11q duplication in cells obtained from different tissues: (1) peripheral blood lymphocytes stimulated with phytohemagglutinin and pokeweed mitogens, (2) epithelial cells obtained from oral mucosa, and (3) epithelial cells obtained from urinary desquamation sediment. The samples were collected by noninvasive methods and were treated following standard procedures to obtain nuclei that were analyzed by FISH. The LSI BIRC3-MALT fusion probe (CytotestTM) was used, which detects the BIRC3 gene located in 11q22.2 (a duplicated region in our patient) with a green fluorochrome, and the MALT gene located on 18q21.32 with a red fluorochrome. The interphase FISH was done according to standardized protocols provided by the manufacturer; at least 100 cells were analyzed.

Dosage-Sensitive Gene Selection and Expression Analysis by qRT-PCR

We selected ClinGen (https://www.clinicalgenome.org) dosage-sensitive genes within the duplicated region 11q13.1q22.3 associated with the clinical features observed in our patient according to the Human Phenotype Ontology (HPO) database (https://hpo.jax.org/app/). Fourteen out of 22 genes were found to be associated, then they were filtered by Gene Cards (https://www.genecards.org) and Human Protein Atlas (https://www.proteinatlas.org) websites to find out the transcript expression of each gene in peripheral blood mononuclear cells (PBMNCs), and in oral mucosal epithelial cells (OMECs), ensuring that each gene included a functional tissue transcriptional regulator (promotor/enhancer) in the duplicated region. A total of five genes to analyze were obtained by this screening: PC, NDUFS8, NDUFV1, TCIRG1, and DHCR7 (online suppl. Table 1; for all online suppl. material, see www.karger.com/doi/10.1159/000528472).

In addition, DECIPHER (https://www.deciphergenomics.org) [Firth et al., 2009] recently recognized 22 triplo-sensitive genes (pTriplo score value ≥0.94) located within the duplicated region 11q13.1q22.3 [Collins et al., 2022]. Five of these genes are related to the proband's phenotype according to the HPO database: KAT5, DPF2, SF3B2, PACS1, and PC (online suppl. Table 1). Due to the limited sample availability, only one triplo-sensitive gene was studied; we selected PC gene which was obtained from ClinGen and DECIPHER curation processes. Finally, since an association between craniofacial malformations and the overexpression of FGF3 and FGF4 has been suggested, these genes were also included in the analysis. Then, a total of seven genes were studied for gene expression.

The gene expression analysis was performed in RNA obtained from non-stimulated PBMNCs and OMECs from the patient and in four unrelated healthy donors with normal karyotype. The RNA was extracted with the RNeasy kit (Qiagen, Hilden, Germany) for PBMNCs and with PureLinkTM RNA Mini Kit (Ambion, Carlsbad, CA, USA) for OMECs; cDNA was obtained by standard methods (Invitrogen, UK). We determined the relative expression of the seven selected genes by qRT-PCR (LightCycler 2.0 Instrument; Roche Applied Science, Germany), and GUSB was used as internal control. All reactions were performed in duplicate. We used the TaqMan gene expression probes from the Universal Probe Library System (Roche Applied Science); the specific probes and primer pairs used are presented in online supplementary Table 2.

Review of Reported Patients with Pure Interstitial Trisomy 11q

To identify previously reported patients with PIT11q, we reviewed and interrogated PubMed, DECIPHER, and NCBIdbVAR (https://www.ncbi.nlm.nih.gov/dbvar) databases using the following criteria. (1) Selection of cases with 11q interstitial duplications, classified as pathogenic or likely pathogenic, which overlap with the duplicated region of our patient (11q13.1q22.3 cytobands or chr11:64798911–110131131 genomic region). (2) Exclusion of all cases with duplications overlapping with the 11q distal region (from 11q23.3 to 11q25) and cases involving another chromosome imbalance.

Cytogenetic and Molecular Characterization

The cytogenetic analysis revealed the karyotype mos 46,XY,dup(11)(q13.1;q22.3)[34]/46,XY[16] in the proband (Fig. 2a). The parents presented normal karyotypes. The multicolor banding FISH confirmed the intrachromosomal duplication and revealed the direct orientation of the duplicated bands (Fig. 2b). The SNP array identified a copy number gain of 45.3 Mb at 11q13.1q22.3 (chr11:64798911−110131131) (Fig. 2c). No additional changes were detected. A high-level mosaicism (>80%) in non-stimulated blood cells was observed in the B allele frequency pattern of the SNP array (Fig. 2c).

Fig. 2.

Cytogenomic characterization of the pure interstitial trisomy 11q in mosaic. a Partial karyotype showing mosaicism with a normal and duplicated chromosome 11. b Multicolor banding FISH showing the normal pattern and the 11q duplication. c SNP array showing a log2 ratio increase at 11q13.1q22.3 (blue rectangle) and BAF allele peaks consistent with the mosaic trisomy pattern.

Fig. 2.

Cytogenomic characterization of the pure interstitial trisomy 11q in mosaic. a Partial karyotype showing mosaicism with a normal and duplicated chromosome 11. b Multicolor banding FISH showing the normal pattern and the 11q duplication. c SNP array showing a log2 ratio increase at 11q13.1q22.3 (blue rectangle) and BAF allele peaks consistent with the mosaic trisomy pattern.

Close modal

The interphase FISH results demonstrated that the 11q duplication was widely distributed among different tissue samples of the proband, such as peripheral blood lymphocytes stimulated with phytohemagglutinin or with pokeweed, OMECs, and urinary desquamation cells, showing frequencies of 46%, 53%, 64%, and 68%, respectively (Fig. 3). The molecular karyotype according to ISCN 2020 was: mos 46,XY,dup(11)(q13.1;q22.3)[34]/46,XY[16].ish dup(11)(q13;q22)(pcp11q++).arr[GRCh37] 11q13.1q22.3(chr11:64798911_110131131)×2∼3 dn. The patient shows a constitutive PIT11q in a high proportion of cells as result of the de novo intrachromosomal duplication.

Fig. 3.

Mosaic distribution analysis on different tissue samples of the patient. Representative images of interphase FISH and mosaic frequencies obtained in peripheral blood lymphocytes stimulated with phytohemagglutinin (PHA-PBLs), pokeweed (PWD-PBLs), oral mucosal epithelial cells (OMECs), or urinary sediment epithelial cells (USECs).

Fig. 3.

Mosaic distribution analysis on different tissue samples of the patient. Representative images of interphase FISH and mosaic frequencies obtained in peripheral blood lymphocytes stimulated with phytohemagglutinin (PHA-PBLs), pokeweed (PWD-PBLs), oral mucosal epithelial cells (OMECs), or urinary sediment epithelial cells (USECs).

Close modal

According to DECIPHER, the duplicated region in our patient contains 651 RefSeq genes, 354 protein-coding genes, and 22 triplo-sensitive genes. While the ClinGen Dosage Sensitivity curation process recognized a total of 22 dosage-sensitive genes non-probed specifically for triplo-sensitivity located inside the duplicated region (online suppl. Table 1).

Gene Expression Analysis

The gene expression analyses revealed no expression of FGF3, FGF4, NDUFS8, or TCIRG1 in any sample. In contrast, PC, NDUFV1, and DHCR7 showed higher expression in the proband’s PBMNCs and/or OMECs compared with the average expression levels found in controls. The PC gene was 3 (PBMNCs) to 18 (OMECs) times overexpressed, the NDUFV1 gene expression was 3 (OMECs) to 24 (PBMNCs) times higher, and DHCR7 gene was 27 (PBMNCs) times overexpressed (Fig. 4).

Fig. 4.

11q dosage-sensitive gene expression levels in the patient and healthy controls. PC, NDUFV1, and DHCR7relative expression in peripheral blood mononuclear cells (PBMNCs) and oral mucosal epithelial cells (OMECs) of the patient (red bars) and the average controls (gray bars).

Fig. 4.

11q dosage-sensitive gene expression levels in the patient and healthy controls. PC, NDUFV1, and DHCR7relative expression in peripheral blood mononuclear cells (PBMNCs) and oral mucosal epithelial cells (OMECs) of the patient (red bars) and the average controls (gray bars).

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Literature Review

The literature review revealed only 8 patients with 11q intrachromosomal duplications overlapping with the duplicated region in our patient, and without involvement of the 11q23.3 to 11q25 distal region (Table 1; Fig. 5). Another 14 cases are reported in specialized databases, unfortunately, not all reports contain detailed information.

Table 1.

Summary of genetic and clinical features in patients with pure interstitial trisomy 11q

 Summary of genetic and clinical features in patients with pure interstitial trisomy 11q
 Summary of genetic and clinical features in patients with pure interstitial trisomy 11q
Fig. 5.

Schematic representation of the 11q duplicated region in the patient and the overlapping literature reports. The cases are placed according to their hg19 genomic coordinates, by the FISH BAC clones ††, or by karyotype defined cytobands †††. The protein-coding gene density (PCGD) graph and the location of the intrachromosomal segmental duplications were obtained from Ensemble database and UCSC Genome Browser, respectively. The dosage-sensitive genes are represented by the arrows and placed according to their genomic position and transcriptional orientation. Among the genes with pTriplo score value ≥0.94 we showed exclusively the genes related to the clinical spectrum of the 11q duplications. SRO, small region of overlap.

Fig. 5.

Schematic representation of the 11q duplicated region in the patient and the overlapping literature reports. The cases are placed according to their hg19 genomic coordinates, by the FISH BAC clones ††, or by karyotype defined cytobands †††. The protein-coding gene density (PCGD) graph and the location of the intrachromosomal segmental duplications were obtained from Ensemble database and UCSC Genome Browser, respectively. The dosage-sensitive genes are represented by the arrows and placed according to their genomic position and transcriptional orientation. Among the genes with pTriplo score value ≥0.94 we showed exclusively the genes related to the clinical spectrum of the 11q duplications. SRO, small region of overlap.

Close modal

We searched for dosage-sensitive genes (DSGs) along the overlapped 11q duplicated regions of our patient, as well as in previous reported cases, to detect and explain the phenotypic characteristics in common. The search revealed 1 patient reported by Jehee et al. [2007], who presents duplication from 11q13.1 to 11q13.3. The patient presents intellectual disability/developmental delay, craniofacial dysmorphology, ophthalmologic defects, dental anomalies, and limb defects; all these features are shared with the present case (Table 1). The overlapping genomic region (chr11:64798911−69500000) included the following DSGs: KAT5, DPF2, SF3B2, PACS1, PC, CLCF, CABP4/2, NDUFV1, NDUFS8, TCIRG1, LRP5, FAAD, IGHMBP2, FGF3, and FGF4 (online suppl. Table 1; Fig. 5). Nevertheless, the patent ductus arteriosus, foramen ovale, and recurrent respiratory infections present in the patient reported by Jehee et al. [2007] are absent in our patient; in addition, no DSGs associated with heart malformations or immunological deficiencies in the non-overlapped region (chr11:56000000−64798911) were found.

In 11q13.3, a small (∼0.43 Mb) overlapping region (chr11:69246102−69685539) was detected. This region contains only two DSGs, FGF3 and FGF4, and comprises the 11q duplication detected in our patient and in the 6 patients described by Legius et al. [1996], Yelavarthi and Zunich [2004], Jehee et al. [2007], Ziebart et al. [2013], and Grillo et al. [2014]. Most of these patients present neurological defects, craniofacial dysmorphology, ophthalmological defects, dental anomalies, and/or congenital heart defects. Remarkable, although some patients share similar duplicated genomic content, the phenotypic features are not always present; this finding suggests variable expressivity or incomplete penetrance (Table 1; Fig. 5).

Finally, the region comprising 11q21 to 11q22.3 overlaps in our patient and in patients reported by Zarate et al. [2007] and Johnson et al. [2015]; this region contains the YAP1 gene, which is associated with mental retardation. Other DSGs present in the region are not related with the PIT11q phenotype or are associated with OMIM syndromes poorly overlapped with the clinical spectrum of the patients.

Here we report a new patient with an uncommon PIT11q derived from an 11q13.1q22.3 intrachromosomal duplication in a high-mosaic state. This is the largest 11q duplication in comparison with others reported (Table 1; Fig. 5). The mechanism of origin is uncertain; however, it could have been promoted by intrachromosomal segmental duplications located near to the breakpoints of the 11q duplicated region (Fig. 5). The 11q duplication probably occurred during the early embryonic development since it was detected with high frequency in tissues from different embryological germ layers (Fig. 3), suggesting that a significant proportion of the patient’s body harbors this rearrangement.

Regarding the genotype-phenotype correlation, the 11q proximal region has a major contribution to the phenotype as it harbors numerous DSGs associated with genetic syndromes, which overlap with the PIT11q clinical spectrum. The duplicated region 11q13.1q13.2 detected in our patient, and in the patient reported by Jehee et al. [2007] concerns four genes associated with autosomal dominant syndromes. These syndromes are characterized by craniofacial dysmorphology, a mild to moderate intellectual disability, delayed dentition, skeletal anomalies and a variable spectrum of cerebral, cardiovascular, and genitourinary malformations (Fig. 5). These four genes are (1) KAT5, which has been associated with the neurodevelopmental disorder with dysmorphic faces, sleep disturbance, and brain anomalies (OMIM #619103); (2) DPF2, which has been related to the Coffin-Siris syndrome 7 (OMIM #618027); (3) SF3B2, associated with craniofacial microsomia (OMIM #164210); and (4) PACS1, correlated with Schuurs-Hoeijmakers syndrome (OMIM #615009). All these genes have a pTriplo score of 1.0, which means a high probability of abnormal function due to the extra copy, suggesting a possible cause to the phenotype of patients with 11q proximal duplications. Regarding the clinical features not shared by our patient and the case reported by Jehee et al. [2007], the discrepancies could be attributed to the mosaic state of the 11q duplications (Table 1).

The PC and NDUFV1 are genes present at 11q13.2, which have been associated with pyruvate carboxylase deficiency syndrome (PCDS; OMIM #266150) and mitochondrial complex I deficiency nuclear type 4 (MC1DN4; OMIM #618225), respectively. Both syndromes are associated with loss of function mutations, which promote a mitochondrial metabolism dysfunction [Mhanni et al., 2021; Zanette et al., 2021]. We detected the overexpression of PC and NDUFV1 in different tissues of our patient, who disclosed some overlapping clinical features with PCDS and MC1DN4 including intellectual disability, developmental delay, and corpus callosum dysgenesis (Table 1; Fig. 4). However, the complex biochemical phenotype being a typical feature of PCDS and MC1DN4 syndromes was not investigated in our patient. Nevertheless, PC has been recently described as a gene with a pTriplo score value of 0.95 indicating a high probability of a deleterious effect due to a gene dosage increase. Therefore, we suggest that the overexpression of PC and NDUFV1 genes may cause a similar PCDS/MC1DN4 phenotype, nonetheless, an accurate biochemical analysis in our patient would be useful to demonstrate this hypothesis and might prove an important area for future research.

The LPR5 gene is located at 11q13.2 and encodes a transmembrane receptor essential for cranial skeleton morphogenesis [Kwee et al., 2005]. Interestingly, Babij et al. [2003] demonstrated that transgenic mice , overexpressing wild-type Lrp5, have higher bone mass compared with normal mice. The present case and the patient reported by Jehee et al. [2007] have an extra copy of LRP5 and craniofacial abnormalities (Fig. 5; Table 1). We hypothesize that the extra allele could conduce to overexpression at early developmental stages, promoting the craniofacial dysmorphology.

The FGF3 gene is located inside the small region of overlapping (Fig. 5), which is associated with the autosomal dominant otodental syndrome (ODS; OMIM #166750). Most of the cases encompassing the FGF3 gene disclose overlapping features with the ODS including craniofacial anomalies and abnormal dentition. Additionally, the FGF3/4 genes have been proposed as osseous developmental malformation genes in patients with PIT11q. We evaluated the expression levels of both genes in different tissues from our patient obtaining negative results. Interestingly, the ortholog genes Fgf3 and Fgf4 are spatiotemporally upregulated in transgenic mouse models with craniofacial dysmorphology that parallels human craniosynostosis syndromes [Carlton et al., 1998]. Considering the positive overexpression results for other DSGs involved in the 11q duplication and the fact that only PBMNCs and OMECS were analyzed, we cannot discard the possibility of the FGF3/4 overexpression in other tissues during the craniofacial morphogenesis process.

We detected the overexpression of DHCR7 in PBMNCs of the proband. The DHCR7 gene is located at 11q13.4 and is associated with the Smith-Lemli-Opitz syndrome (SLOS; OMIM #270400). Our patient and those reported by Legius et al., [1996] and Yelavarthi and Zunich [2004] disclosed various overlapping features with SLOS clinical spectrum, including intellectual disability, developmental delay, ventral septal defect, corpus callosum dysgenesis, and cryptorchidism (Fig. 5; Table 1). Interestingly, Prabhu et al. [2016] proved that in vitro overexpression of DHCR7 reduces the enzyme activity by proteasomal degradation; however, DHCR7 mRNA levels are not diminished, suggesting that the overexpression of DHCR7 modifies cholesterol balance, which is the pathogenic base of the SLOS phenotype. Further research in in vivo models is required to analyze the phenotypic consequences of DHCR7 overexpression.

Finally, at 11q22.1, the YAP1 gene is associated with autosomal dominant mental retardation, but also with coloboma, hearing impairment, and cleft lip/palate (OMIM #120433). These features are absent in patients with duplication of this gene, but mental retardation could be absent or present in a mild form, suggesting incomplete penetrance (Fig. 5; Table 1). Remarkably, the duplication of the 11q21q22.3 region seems to have a minor contribution to the PIT11q phenotype, considering the mild/normal intelligence and the minor dysmorphic features of the patient described by Zarate et al. [2007] and Johnson et al. [2015]. This mild phenotype could be related to the absence of triplo-sensitive genes or to the minor protein-coding gene density of the 11q14.1q22.3 region compared with the 11q11q13.5 region (Fig. 5; Table 1). Furthermore, mild or absence of phenotypic abnormalities has been described in carriers of deletions encompassing the 11q14.3q21 region, supporting the innocuous nature of the chromosomal imbalances in that region [Li et al., 2002].

In conclusion, we report a new case with PIT11q by an intrachromosomal mosaic duplication characterized through cytogenomic methods. Contrasting to previous reports, we confirmed the overexpression of DSGs involved in the duplicated region and provided a detailed clinical review and an accurate genotype-phenotype correlation for the 11q interstitial region, including triplo-sensitive genes involved in the PIT11q clinical spectrum. We also contribute to the delineation of the PIT11q phenotype since our patient exhibits genital anomalies, which are clinical features that have not been previously described in these patients. However, the clinical manifestations vary in each patient, even when they share similar regions with trisomy. This genetic entity is very uncommon and further work is required to improve the description, considering the relationship between the chromosome segment and the genes involved.

We thank the patient’s family, CONACyT (SALUD-17-01-289930-01-008), and Recursos Fiscales para Investigación INP 2021.

Written informed consent was obtained from the parents of the patient for all genetic tests, photographs, and to publish this case, according to the recommendations of the Helsinki Declaration. This study protocol was reviewed and approved by the Research and Ethics Committees with National Commission of Bioethics registration number “CONBIOETICA-09-CEI-025-20161215” of National Pediatric Institute.

The authors have no conflicts of interest to declare.

The study was funded by CONACyT (SALUD-17-01-289930-01-008) and Recursos Fiscales para Investigación Instituto Nacional de Pediatría 2021.

Daniel Martínez Anaya conceived the present study, performed the cytogenetic and FISH analyses in different tissues, and designed the figures. Sinuhé Reyes Ruvalcaba and Esther Lieberman Hernández diagnosed the patient, obtained the clinical data, and contributed to the critical clinical analysis of the reported cases. María del Pilar Navarrete-Meneses performed the MCB-FISH analysis. María del Rocío Juárez-Velázquez performed the gene expression analysis. Consuelo Salas Labadía interpreted the cytogenomic data. Esther Lieberman Hernández and Patricia Pérez-Vera conceived the present idea and discussed the results. All authors participated in drafting the manuscript.

All generated or analyzed data are included in this article and its online supplementary material. Further inquires can be directed to the corresponding authors.

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