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clino-brachydactyly [Figures 1A and B and 2A and B, Table 1], as reported in all patients with a deletion
including entirely DNM3 [1-2,4,6] [Figures 5B-D and 6A].

In agreement with our data, our probability distribution profiles indicate that deletions for the proximal
portion of SRO-D (chr1:177,238,295-178,548,677), indicated as No. 3 (SRO-3, Table 2), are significantly
associated with microcephaly, ID, and short hands/feet [Figures 5A-C and 6A]; less with brachydactyly
[Figures 5B and 6A], micro/retrognathia and hypertelorism; and not associated at all with kidney
abnormalities, hypotonia, speech and walk delay, and dysplastic ears [Supplementary Figures 4 and 5].

BRINP2/FAM5B is the only gene of the region that is intolerant to haploinsufficiency but its role is
unknown [Figure 6E and Supplementary Table 4].

In contrast, our probability distribution profiles indicate that deletions for the distal portion of SRO-D
are significantly associated only with ID and brachydactyly [Figures 5A and 6A], although it should be
noted that the microcephaly area of probability does not encompass this region due to the dubious effect
of the deletion in our Patient 5. This region includes CEP350, RALGPS2, TDRD5, and XPR1 genes that are
intolerant to haploinsufficiency; all have a low brain expression but none of them is thus far recognized
as a disease gene [Supplementary Table 4]. In addition, LIM homeobox 4 (LHX4, OMIM 602146), a gene
[26]
implicated in the etiology of congenital hypopituitarism (OMIM #262700), was previously evoked as
possible candidate gene for growth deficiency [7,27] .

[1]
Altogether, we have to assume that deletion for the proximal region 1q23.3q24.1 (SRO-P ) is associated
with kidney anomalies of high penetrance for total PBX1 loss [Supplementary Figures 4 and 5] and ID but
not microcephaly [Figure 5]. Microcephaly is fully associated with deletions of more than one SROs (SRO-2,
-I, and -D, Figures 6 and 7) and the most favorable new candidate gene is ATP1B1 in SRO-2.

Cases 5 and 6 are puzzling for the apparently different phenotypes in the presence of identical deletion.
Indeed, Case 5 is a healthy adult and Case 6 is still a newborn with a nuanced disorder and perhaps would
have been considered healthy if we had not incidentally identified the deletion in the father. Among genes
mapping in their 5.9-Mb deleted region, between 172,667,560 and 178,548,677 [Supplementary Table 5],
at least two are associated with systemic diseases: TNFSF4 (MIM *603594), related to systemic lupus
erythematosus (OMIM#152700), and DARS2 (MIM*610956), involved in recessive leukoencephalopathy
with brainstem and spinal cord involvement and lactate elevation (MIM#611115). None of these conditions
were consistent with the clinical presentation of our Cases 5 and 6. We reasoned that the deletion might
have unmasked a maternally inherited recessive variant in that region. However, WES analysis on the
mother did not support this hypothesis, suggesting that other genetic or environmental factors may
modulate the phenotype associated with this deletion. Indeed, the microcephaly, which is the main feature,
observed in our Case 6, is a neurological sign that may be caused by a multitude of disease-causing genes
[28]
with recessive or dominant inheritance . However, by WES, we did not highlight any possible pathogenic
variants in all genes associated with microcephaly having a frequency < 1% that could explain this trait in
[28]
our Case 6.

Similarly, IUGR, which characterized the prenatal life of our Case 6, is an end result of various etiologies
that include maternal, placental, fetal, and genetic factors . Looking at the clinical history of our family
[29]
[Figure 3], IUGR was documented not only in the child carrying the 1q deletion, but also in her brother
without this deletion (Subject III.2), and even in the IUFD at 39th week of gestation (Subject III.3). Indeed,
by WES data, we identified in the mother’s genome, two heterozygous missense variants, c.796C>T:p.
R266W and c.1279G>A:p.A427T in TXBAS1 [Supplementary Figure 3], a gene having a possible role
in thrombotic events [30,31] . Since both variants are rare (AF< 0.001%), predicted deleterious in several