Discussion
The cytogenetic band 2q13 is enriched in clusters of highly homologous
sequences, which facilitate the occurrence of deletions and/or
duplications, quite recurrent in size and breakpoints (Hladilkowa,
2015). Among these rearrangements, a recurrent 1.71 Mb deletion is
associated with a congenital syndrome (around 50 patients reported to
date) manifesting with variable phenotype, which includes psychomotor
development disabilities, mild craniofacial dysmorphisms and CHD, and
currently defined as 2q13 deletion or microdeletion syndrome (Wolfe,
2018; Guivarch, 2018).
The phenotype of the present patient (showing craniofacial dysmorphisms,
CHD and neurodevelopmental delay), although being overlapping with that
of most 2q13 deletion subjects described to date, seems to be more
severe (specifically for the eye and ear involvement), sharing clinical
signs with the oculo-auricular-vertebral spectrum (OAVS). This latter
disorder affects craniofacial morphogenesis, and involves structures
derived from the first and second pharyngeal arches (Passos-Bueno,
2009). Its manifestations include asymmetric ear anomalies with or
without hearing loss, hemifacial microsomia resulting in facial
asymmetry, orofacial clefts, ocular (including epibulbar dermoids) and
vertebral defects. Cardiac, genitourinary and cerebral malformations may
be associated. Several chromosomal/genomic anomalies are observed in
patients showing an OAVS phenotype. However, 2q13 deletions are not
reported (Beleza-Meireles, 2014).
The deleted region of our patient encompasses eleven genes, nine protein
coding ones (BUB 1 partially deleted, ACOXL1 ,BCL211 , MERTK , FBLN7 , TMEM87B ,ANAPC1 , ZC3H8 and ZC3H6 ), and two coding for
microRNA (miRNAs, MIR4435-2HG and MIR4771-2 ).
The dysmorphism and head circumference anomaly generally observed in
cases with this deletion may depend on FBLN7 (fibulin 7)
haploinsufficiency. This gene encodes fibulin-7, a glycoprotein which
plays a role in the formation of facial bones (Guivarch, 2018). Its
involvement may explain the hemifacial hypoplasia of our newborn,
showing also absent uvula and small chin, as well as homolateral eye and
ear involvement. Fibulin-7 cooperates with other proteins involved in
heart development. Such function may clarify the association with CHDs
reported in 2q13 deletion patients (Russell, 2014), and observed also in
our newborn. TMEM87B (transmembrane protein 87B) is likely
related with developmental delays, autism spectrum disorders (ASDs), and
other psychiatric phenotypes as well as CHD (Guivarch, 2018; Yu, 2016;
Russell, 2014), and its defect may be consistent with the neurological
(generalized hypotonia and feeding difficulties) and cardiac findings of
our patient. Disruption of ACOXL (acyl-CoA oxidase like,
affecting fatty acid metabolism) (Wolfe, 2018; Yu, 2012) andBCL2L11 (BCL2 like 11, which encodes an antiapoptotic protein
expressed in the frontal cortex and in the cerebellum, thus increasing
apoptosis and the correlated risk of ASDs) (Sheikh, 2010) may contribute
to neurodevelopmental and ASD phenotypes of these subjects (Wolfe, 2018;
Yu, 2012). ANAPC1 (anaphase promoting complex subunit 1), a
neurodevelopmental facilitator mainly expressed in the brain and the
lymphoid organs, and MERTK (MER proto-oncogene, tyrosine kinase)
are candidate genes for the psychosis phenotype of 2q13 CNV carriers
(Wolfe, 2018). The latter is also associated with retinal defects and
autosomal recessive retinitis pigmentosa. It may have, thus, a role in
the ocular development, which is disrupted (epibulbar dermoid) in our
patient.
In the rearranged DNA of our newborn there are also two genes coding for
miRNAs, that may influence the expression of the phenotype. They are
short (20-24 nt) non-coding RNAs, that are involved in
post-transcriptional regulation gene expression. Between them, theMIR4435-2HG gene is ubiquitously expressed in different tissues,
mainly brain, heart and lymphoid organs. In the latter ones are also
highly expressed ZC3H8 and ZC3H6 (zinc finger CCCH-type
containing 8/6). Defects in one of these genes may cause a greater
predisposition to infections (including otitis), and contribute to the
phenotype of our proband, as well as to that of 2q13 deletion patients,
in which such risk is described (Wolfe, 2018).
Several explanations for the variable expressivity (Girirajan, 2012) and
reduced penetrance observed in 2q13 deletion patients are supposed, such
as differences in gene content due to variable deletion breakpoints
(Hladilkova, 2015). Specifically, a more severe clinical expressivity
(like that showed by our newborn, including craniofacial dysmorphisms,
ocular involvement with epibulbar dermoid and vertebral lumbar kyphosis)
occurs because of the combined loss of more candidate genes present in
the critical rearrangement (Russell, 2014). However, localization and
width of such recurrent deletion is quite overlapping among the patients
described in the literature. Therefore, besides the possible role played
by genes contiguous to the deleted region (as occur in contiguous gene
syndromes), there could be other plausible causes: in the “two hit”
hypothesis, the 2q13 deletion could represent a “first hit” (i.e. a
risk factor) for a second one, represented by an additional genomic
imbalance (deletions and/or duplications), observed in some of the
patients described to date (Hladilkova, 2015), but which is absent in
our proband; otherwise, other genomic mutations may unmask recessive
alleles.
In the present patient, as whole genome sequencing was not performed, it
cannot be ruled out that another genetic variant was contributing (or
modify) to her phenotype. Moreover, epigenetic factors may also
exacerbate the expressivity of the clinical picture (Guivarch, 2018).
Our report is the first description of an OAVS phenotype in a 2q13
microdeletion patient. We cannot establish to date if such association
is casual, or if a genetic bond exists between them. In regard to this,
it could be supposed that loss of FBLN7 , which is expressed in
the branchial arches (Russell, 2014), may be associated with development
anomalies of the structures derived from the first and second pharyngeal
arches (which are affected, indeed, in the OAVS).
Moreover, a further research on FBLN7 gene networks
(https://genemania.org/search/homo-sapiens/FBLN7/, access 05/07/2020)
identified a physical interaction network involving 3 genes
(EDEM2 , ASPH , CLNS1A ), a co-expression network
involving 17 genes (GLYATL2 , IZUMO2 , SMYD2 ,BMPER , AHDC1 , PRELID2 , NEIL1 , MDGA1 ,TLL1 , TTC6 , CDH7 , EMID1 , G6PC2 ,SH3GL3 , AMBN , DOC2A , BCL7A ), and a shared
protein domain network involving TLL1 . Among the aforementioned
genes, three are associated with clinical phenotypes overlapping with
the 2q13 deletion syndrome: TLL1 (cardiac malformations),ADHC1 (hypotonia, corpus callosum hypoplasia) and ASPH(facial dysmorphism). No FBLN7 gene pathway has been described
yet.
This report may provide useful data about the clinical and genomic
features of 2q13 deletions, and expand the phenotypes associated with
this rearrangement, which does not have to date a recognizable set of
specific manifestations (Riley, 2015). It strengthens the importance of
microarray analysis in cases of congenital malformations and/or
dysmorphic features without a clinical picture suggestive for known
disease (Pavone, 2019; Pavone, 2019; Viaggi, 2012).
Obtaining an early genetic diagnosis in the neonatal age, like occurred
in the present case, is relevant for proper management of the patient,
which includes individualized follow-up (enabling prevention of future
comorbidities, such as infections, hearing loss, orthopedic and
neuropsychiatric disorders) and genetic counseling for the family
(recurrence risk for later pregnancies) (Lefebvre, 2016).
Further functional studies of the 2q13 genes, identification of single
gene mutations (Iyer, 2015), as well as extended comparative analysis of
a larger number of age-matched patients with overlapping features, may
allow a more precise clinical and genomic characterization (Corsello,
2018). This is also useful to define genotype-phenotype correlations
(Serra, 2019).