Abstract
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.
1. Introduction
Chromosomal abnormalities, involving the short arm of chromosome 10, have been rarely reported. Only 13 patients with large overlapping deletions of 10p11.2-p12 have been described in the literature [,,,,,,]. 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) [].
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 [].
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 [,,,,,,], the same cannot be said for the case of genetic modification.
2. Materials and Methods
2.1. 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.
2.2. 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).
3. Results
Chromosomal Q-banding revealed a karyotype of 46,XX, del(10)(p11.2p11.2) (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.
A comparative genomic hybridization (aCGH) array test was performed to establish the breakpoints of the deletion. The CGH array showed the presence of a heterozygous deletion of approximately 5.7 Mb in size at 10p11.21-p11.22: arr[GRCh37]10p11.22p11.21(31615276_37385312)x1 (Figure 2).
Figure 2.
aCGH detected a 5.7 Mb chromosomal deletion in the region of 10p11.21-p11.22 (blue box).
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.
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.
4. Discussion
Here, we report the case of a deletion in a female child aged 5 years old, encompassing 23 genes in the 10p11.2 band. 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 []. 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) []. To date, about 13 patients with large overlapping deletions of 10p11.2-p12 have been described in the literature [,,,,,,]. None of these patients share common breakpoints, but Abdelhedi et al. [] 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 []. 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 [].
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.
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.
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.
Figure 3.
Schematic illustration of chromosome 10 showing the deletions at 10p12p11 in the patients described in the literature (1 patient by Shadadpuri et al., 2008 []; 6 patients by Wentzel et al., 2011 []; 2 by Okamoto et al., 2012 []; 1 by Mroczkowski et al., 2014 []; 1 by Abdelhedi et al., 2016 []; 1 by Toledo-Gotor et al., 2022 []; and 1 by Bolat et al., 2022 []) with the patient described in this study. The smallest region of overlap (SRO) identified by Abdelhedi et al. (2016) [] is indicated by vertical blue dotted lines, while vertical red dotted lines identified patients with overlapping deletion with the patient of this study. The red stars indicated the OMIM genes involved in patient’s deletion.
5. 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.
Author Contributions
Conceptualization, G.S., C.L., M.I. and D.Z.; methodology, G.S. and M.I.; software, E.S., S.C., G.S. and M.P.; validation, S.C., E.S. and M.P.; formal analysis, S.C. and G.S.; investigation, I.G., E.S., S.C. and D.Z.; resources, C.L., D.Z. and M.F.; data curation, G.S.; writing—original draft preparation, G.S., I.G. and E.S.; writing—review and editing, M.I. and M.F.; visualization, G.S.; supervision, G.S., M.I. and M.F.; project administration, C.L. and M.I.; funding acquisition, C.L., D.Z. and M.F. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent was obtained from the parents of the subject involved in the study.
Data Availability Statement
Raw data were generated in the laboratory of Synlab Italy (Castenedolo, BS, Italy). The data derived supporting the findings of this study are available from the corresponding author upon request.
Conflicts of Interest
The authors declare no conflicts of interest.
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