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databases, and almost certainly in trans, only one being present in the first son of the couple, the two
variants most likely represent a risk factor for the recurrent pregnancy losses and IUGR observed in this
family.

Taken together, the link between 1q deletion identified in this family and the phenotype in our patient
remains elusive. A long-term clinical follow-up of our newborn patient will help to clarify whether this
deletion represents a benign CNV or a rearrangement showing incomplete penetrance.

In conclusion, we confirmed and identified several genes whose haploinsufficiency appears crucial in the
manifestation of the main phenotypic abnormalities associated with 1q23.3q25.2 deletions [Supplementary
Table 6]. In particular, PBX1, in addition to its well-known role in kidney abnormalities, is strongly
associated with ID and contributes to the behavioral traits along with psychiatric disorders. DNM3 and
LHX4 are hereby confirmed as responsible for growth retardation [7,27] while ATP1B1 represents a new
candidate gene for microcephaly.

It should however be underlined that, apart from SRO-1, the other three SROs contain genes belonging to
different TADS, some of which are interrupted by the deletion (http://3dgenome.org).

We cannot therefore rule out that some phenotypic abnormalities are due to an altered expression of some
of the non-deleted genes following the breakdown of the TADs, rather than the haploinsufficiency of
[32]
specific genes .

Finally, we propose a method to computationally predict the probability that a given DL lies in a specific
genomic segment. Although this approach may be hampered by long-term position effects of regulatory
elements, synergistic cooperation of several genes, and incomplete clinical assessment, it can be useful,
especially for contiguous gene syndromes that show a complex pattern of clinical characteristics. Obviously,
functional approaches are needed to warrant its reliability.

DECLARATIONS
Acknowledgments
We would like to gratefully acknowledge the family participating in this study.
We thank Dr. Lucialba Rapisarda, expert in modeling and simulation of complex systems, for her useful
advice in preparing probability related graphs.

Authors’ contributions
Made substantial contributions to conception and design of the study, performed data analysis and
interpretation, wrote the original draft: Fichera M, Bonaglia MC
Investigation: Saccuzzo L, Bertuzzo S, Cavallini A, Bonaglia MC

Provided clinical data: Marelli S, Cavallini A, Romaniello R, Kocova M, Citterio A, Fanizza I, Trabacca A,
Pagliazzi A, Guarducci S, Giglio S
Writing - Review & Editing: Fichera M, Zuffardi O, Bonaglia MC
Supervision and acquisition of the financial support for the project leading to this publication: Bonaglia
MC

Availability of data and materials
Data supporting our findings are published as supplementary information in the journal.
The software is available on request.

Financial support and sponsorship
This work was supported by the Italian Ministry of Health (2758027) to Bonaglia MC.