An Unclassified Deletion Involving the Proximal Short Arm of Chromosome 10: A New Syndrome?

To date, only 13 studies have described patients with large overlapping deletions of 10p11.2-p12. These individuals shared a common phenotype characterized by intellectual disability, developmental delay, distinct facial dysmorphic features, abnormal behaviour, visual impairment, cardiac malformation, and cryptorchidism in males. Molecular cytogenetic analysis revealed that the deletion in this chromosomal region shares a common smallest region of overlap (SRO) of 80 kb, which contains only the WAC gene (WW-domain-containing adaptor with coiled coil). In this clinical case report, we report a 5-year-old girl, born from non-consanguineous parents, with a 10p11.22p11.21 microdeletion. She presents clinical features that overlap with other patients described in the literature, such as dysmorphic traits, speech delay, and behavioural abnormalities (hyperactivity), even though the WAC gene is not involved in the microdeletion. Our results are the first to highlight that the deletion described here represents a contiguous gene syndrome that is enough to explain the distinct phenotype but partially overlaps with the previous cases reported in the literature, even though the same genes are not involved. In particular, in this study, we speculate about the role of the WAC gene that seems to be associated with normal motor development. In fact, we found that our patient is the only one described in the literature with a large deletion in the 10p11.22p11.21 region without the involvement of the WAC gene deletion, and, interestingly, the patient did not have motor delay.


Introduction
Chromosomal abnormalities, involving the short arm of chromosome 10, have been rarely reported.Only 13 patients with large overlapping deletions of 10p11.2-p12have been described in the literature [1][2][3][4][5][6][7].These individuals shared a common phenotype characterized by intellectual disability, developmental delay, distinct facial dysmorphic features, abnormal behaviour, visual impairment, cardiac malformation, and cryptorchidism in males.Molecular cytogenetic analysis revealed that the deletion in this chromosomal region shares a common smallest region of overlap (SRO) of 80 kb, which only contains the WAC gene (WW-domain-containing adaptor with coiled coil) (OMIM #615049) [5].
Karyotype is the gold standard for analysing the detection of numerical chromosomal abnormalities (aneuploidies) and structural chromosomal rearrangements.At the 500-550 band level, the limit for detecting genomic rearrangements is expected to be above 5-10 Mb, while copy number variation (CNV) analysis is nowadays routinely offered to patients with developmental delay, autistic spectrum disorder, and dysmorphic features because it is useful for the detection of chromosomal rearrangements smaller than 5 Mb.
The recurrent CNVs associated with new syndromes are often related to abnormalities in a region that show a variable size and breakpoints with only some small areas of overlap, in which genes that seem to determine the phenotype are shared [8].
Here, we report a female 5-year-old child with a microdeletion in 10p11.22p11.21.Although this patient exhibited dysmorphic traits, speech delay, and behavioural abnormalities (hyperactivity) that overlap with other clinical cases described in the literature [1][2][3][4][5][6][7], the same cannot be said for the case of genetic modification.

Clinical Report
The female patient was the first child born to non-consanguineous healthy parents.The mother and the father were 39 and 56 years old, respectively, at the time of the patient's birth.She presented severe plagiocephaly, facial asymmetry, prognathism and an open bite, epicanthus, long palpebral fissures, a bulbous nasal tip, cupped ears, a short neck, a bilateral single palmar crease, flat feet, and visual defects (photo not shown).Moreover, she had small-joint laxity, as well as soft and elastic skin.After genetic counselling, the geneticist suspected a chromosomal anomaly and suggested Karyotype analysis.The patient underwent genetic testing after written informed consent was obtained from her parents.

Cytogenetic Analyses
The conventional karyotyping of peripheral blood lymphocytes was performed using Q-band analysis.The result was further validated through array CGH, which accurately detected the breakpoints of the deletion, the genomic size, and the genes involved.aCGH analysis was carried out using a whole-genome 4 × 180 K oligonucleotide microarray platform containing over 170,334 distinct biological probes annotated against NCBI Build 37 (UCSC hg19, February 2009) from Agilent Technologies (5301 Stevens Creek Blvd Santa Clara, CA 95051 United States).Samples from the patient and her parents were hybridized against a same-sex hybridization control (human reference DNA, from Agilent Technologies).

Results
Chromosomal Q-banding revealed a karyotype of 46,XX, del(10)(p11.2p11.2) (Figure 1).This deletion was never classified before; it expands from 10p11.22 t encompassing 23 genes (Table 1), of which 13 are listed in the OMIM databa bold).This deletion was never classified before; it expands from 10p11.22 to 10p11.21,encompassing 23 genes (Table 1), of which 13 are listed in the OMIM database (Table 1, bold).Table 1.The 23 genes involved in the patient deletion: 13 OMIM genes in bold black and the only gene associated with a Mendelian autosomal dominant disease in bold red.

Gene
Protein Name Protein Function Gene Ontology

Zinc Finger E-Box-Binding Homeobox
The encoded protein seems to contribute to the transcriptional inhibition of interleukin 2. Pathogenic variants in this gene have been linked to late-onset Fuchs endothelial corneal dystrophy and posterior polymorphous corneal dystrophy-3.This gene encodes for a member of the PARD protein family.They affect asymmetrical cell division and direct polarized cell growth.

Nucleic acid binding
Protein phosphatase binding and phosphatidylinositol-4,5bisphosphate binding

PARD3-AS1 PARD3-Divergent Transcript
This is an RNA gene and is affiliated with the lncRNA class.None

CUL2
Cullin 2 A part of Cul2-RING ubiquitin ligase complex.It is predicted to be involved in SCF-dependent proteasomal ubiquitin-dependent protein catabolic processes and protein ubiquitination.It is also predicted to act upstream of, or within, the protein catabolic process.
Ubiquitin protein ligase binding and protein-containing complex binding

MIR3611
MicroRNA 3611 It is an RNA gene and is affiliated with the miRNA class.None Table 1.Cont.

CAMP-Responsive Element Modulator
This gene codes for a bZIP transcription factor crucial in cAMP-mediated signal transduction during the spermatogenetic cycle and other processes.
DNA-binding transcription factor activity and core promoter sequence-specific DNA binding

Cyclin Y
This protein is the CDK14/PFTK1 and CDK16 cyclin-dependent kinase's positive regulatory subunit that functions as a Wnt signalling pathway cell-cycle regulator.
Protein kinase binding and cyclin-dependent protein serine/threonine kinase regulator activity

GJD4
Gap Junction Protein Delta 4 The encoded protein participates in creating gap junctions, which are intercellular channels that directly link the cytoplasms of contacting cells.

FZD8
Frizzled Class Receptor 8 This intronless gene, belonging to the frizzled gene family, encodes a seven-transmembrane domain protein acting as a receptor for wingless-type MMTV integration site family signalling proteins, which are commonly linked to the β-catenin canonical signalling pathway.

None
Then, we performed aCGH on the DNA extracted from the parents' peripheral blood.Their normal CMA led us to conclude that the deletion at 10p11.21-p11.22 was de novo.

Discussion
Here, we report the case of a deletion in a female child aged 5 years old, encompassing 23 genes in the 10p11.2band.It is known that deletions involving the proximal short arm of chromosome 10 (10p11-p12) are associated with a rare genetic syndromic intellectual disability characterized by developmental delay, hypotonia, speech delay, mild-to-moderate intellectual disability, abnormal behaviour (autistic, aggressive, and hyperactive), and dysmorphic facial features.Congenital heart and brain anomalies, as well as visual and hearing impairment, are also common [1].In 2011, Wentzel et al. speculated that non-homologous end-joining or FoSTeS might likely be the mechanisms for the recurrence of deletions in this region of chromosome 10, as the breakpoints do not contain any segmental duplications required for NAHR (hon-allelic homologous recombination) [2].To date, about 13 patients with large overlapping deletions of 10p11.2-p12have been described in the literature [1][2][3][4][5][6][7].None of these patients share common breakpoints, but Abdelhedi et al. [5] redefined a new smallest region of overlap (SRO) that contains only the WAC gene, thus underlining the importance of this gene in some of the clinical features of these patients, such as intellectual disability and developmental delay.The WAC gene encodes the WW-domain-containing adaptor with the coiled-coil region, a nuclear protein that is known to be important in a wide variety of processes, such as gene transcription, microtubule development, autophagy, and Golgi apparatus function [9].Loss-of-function variants associated with the WAC protein are also associated with DeSanto-Shinawi syndrome, a neurodevelopmental disorder whose clinical features overlap with a large deletion involving this gene [6].
In this study, the chromosomal deletion 10p was found to contain 23 genes, 13 of which are listed in the OMIM database.Interestingly, in this case study, unlike other similar cases reported in the literature, the WAC gene, described as the only gene in the SRO region, was not involved in the 10p11-p12 deletion.Although our patient exhibited speech delay, abnormal behaviour (hyperactive), several dysmorphic features, and visual impairment, similar to the majority of patients described in the literature (Table 2), she did not have motor delay.Based on this latest clinical evidence and the absence of the deletion of the WAC gene, we speculate that the WAC gene could play a role in normal motor development as our patient started to walk independently from the age of 12 months.
Furthermore, although the clinical features of the patient described in this study overlapped with those described in the literature, we found that the genes involved were different.In particular, the patient's deletion overlapped only with three cases described before, but it was the smallest one (Figure 3) and did not share the WAC gene associated with the phenotype, as reported in the literature.The patient differed from the other three patients in the absence of developmental delay and cardiac abnormalities.However, both our patient and the three other patients shared visual impairment and some facial dysmorphisms.For example, bulbous nasal tip was observed in patient 4 by Wentzel et al. and in the patient described by Shahdadpuri et al., and a short neck and epichantus were observed in patient 5 by Wentzel et al.These differences and similarities suggest a complex genotype-phenotype correlation, underscoring the importance of thorough clinical assessment and genetic analysis in understanding and managing these conditions.

Conclusions
In conclusion, we propose that the deletion described here represents a contiguous gene syndrome that is enough to explain the distinct phenotype that partially overlaps with the previous cases reported in the literature, even though different genes are involved.In particular, the WAC gene seems to be associated with normal motor development as our patient is the only patient described in the literature with a large deletion in this chromosomal region with the absence of a WAC gene deletion and that did not have motor delay.However, it would be useful to further investigate this region to better understand the exact genotype-phenotype correlations.

Conclusions
In conclusion, we propose that the deletion described here represents a contiguous gene syndrome that is enough to explain the distinct phenotype that partially overlaps with the previous cases reported in the literature, even though different genes are involved.In particular, the WAC gene seems to be associated with normal motor development as our patient is the only patient described in the literature with a large deletion in this chromosomal region with the absence of a WAC gene deletion and that did not have motor delay.However, it would be useful to further investigate this region to better understand the exact genotype-phenotype correlations.

Figure 1 .
Figure 1.Karyotype of the patient with del(10)(p11.2p11.2).The numbers refer to each couple of homologous chromosomes.The arrow indicates the chromosome involved in the deletion.

Figure 1 .
Figure 1.Karyotype of the patient with del (10)(p11.2p11.2).The numbers refer to ea homologous chromosomes.The arrow indicates the chromosome involved in the dele
our patient and the three other patients shared visual impairment and some facial dys-morphisms.For example, bulbous nasal tip was observed in patient 4 by Wentzel et al. and in the patient described by Shahdadpuri et al., and a short neck and epichantus were observed in patient 5 by Wentzel et al.These differences and similarities suggest a complex genotype-phenotype correlation, underscoring the importance of thorough clinical assessment and genetic analysis in understanding and managing these conditions.

Table 2 .
Summary of the clinical features of our case and of previous cases described in the literature affected by the 10p12.1-p11.23 deletion.