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Fichera et al. J Transl Genet Genom 2020;4:114-32 I http://dx.doi.org/10.20517/jtgg.2020.16 Page 115

Methods: Merging cases with those in the literature, we considered four traits, namely intellectual disability (ID),
microcephaly, short-hands/feet, and brachydactyly, and conceived a mathematical model to predict with what
probability the haploinsufficiency of a specific portion of the deletion region is associated with one of the four
malformations.

Results: The haploinsufficiency of PBX1 is strongly associated with ID. DNM3 and LHX4 are confirmed as
responsible for growth retardation, whereas ATPIB1 was identified as a new candidate gene for microcephaly,
short-hands/feet, and brachydactyly.

Conclusion: Although our model is hampered by long-term position effects of regulatory elements, synergistic
cooperation of several genes, and incomplete clinical assessment, it can be useful for contiguous gene syndromes
showing a complex pattern of clinical characteristics. Obviously, functional approaches are needed to warrant its
reliability.

Keywords: PBX1 , genotype-phenotype, haploinsufficiency, incomplete penetrance, ATP1B1 , microcephaly,
contiguous gene syndrome

INTRODUCTION
The usual method to identify the shortest regions of overlap (SRO) in contiguous gene syndromes relies on
the graphical identification of the area of minimal overlap between deletions in patients sharing the same
phenotype. Although this approach is very efficient when dealing with traits present in all the subjects
who share the deletion region, it is much less productive when the trait is shared by some of the patients
only. The usual way to overcome this uncertain correlation is to attribute an incomplete penetrance to the
trait, a definition that may hide multiple factors such as the influence of any other genetic factors necessary
for the manifestation of the trait, the differences in the breakpoints of the deletion involving any different
dynamics of chromatin interactions between enhancers and promoters, environmental factors, or more
simply inaccurate assignment of phenotype. Obviously, “non-penetrant” deletions may either overlap
the disease locus (DL) or not include it, so that they constitute a limitation to defining SRO boundaries.
However, they still strongly modulate the probability profile of the DL location along the SRO, i.e., the
probability for the DL to map at a given position, considering the whole body of experimental data (i.e.,
all the deletions, either penetrant or non-penetrant, overlapping a given genomic position inside the
SRO). In fact, the trait(s) considered in a given genomic region are often de novo and present in restricted
numbers of subjects, so that the exclusion of even a single case can really be limiting to a correct locus
assignment. Therefore, it is highly desirable to find a probabilistic model that, by considering also the
“non-penetrant” cases, makes more reliable the assignment of specific traits to specific genomic portions.
For this purpose, we propose a new genotype-phenotype correlation approach, applying our statistical
procedure to interstitial deletions of 1q23.3-q25, of which more than 30 cases have been reported, with
the imbalance being mainly de novo with the exception of three subjects who have inherited the deletion
[3]
[1]
[2]
from the affected mother (Patients P10 and P17 , Patient A , and Case 1 ). These deletions are associated
with a complex malformation condition consisting in proportionate pre- and postnatal growth deficit,
cardiac malformations, small hands and feet with brachydactyly, intellectual disability (ID) of various
degrees, and craniofacial dysmorphisms such as microcephaly, micrognathia, short nose with bulbous tip,
dysplastic ears, elongated upper lip, and small chin have been reported in most subjects [1,3] . The relationship
between the size and localization of the copy number variants and phenotypic abnormalities in thirty-five
patients [1-9] allowed identifying three non-overlapping regions whose haploinsufficiency seemed crucial for
[1]
the manifestation of some specific characteristics . The SRO associated with growth and developmental
[2]
[4]
delay has been progressively narrowed from 1.9 Mb to a 179-kb region (chr1:172,460,683-72,281,412 hg19) .