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Page 128 Fichera et al. J Transl Genet Genom 2020;4:114-32 I http://dx.doi.org/10.20517/jtgg.2020.16

2-4 and in patients reported with overlapping 1q deletions including both the intermediate and distal SROs
[Table 1].

Figures 5 and 6 illustrate the new SROs we defined according to the genotype-phenotype correlations
emerging from our study.

SRO-P (chr1:164,501,003-167,022,133) was narrowed from 2.7 Mb to 38 kb (chr1:164,761,881-164,799,811)
within a region involving exons 4-8 of PBX1 that in Figure 6A and B is indicated as N.1.

This deletion is common to the 17 cases, including our Case 1, listed with an asterisk in Figure 5A with
deletions ranging from 276 kb to 14.1 Mb. All have from severe to moderate ID but not microcephaly
[Figure 5B]. The probability mass distribution at this region, as computationally calculated according to
methods [Supplementary Table 2], shows that highest values for ID, kidney abnormalities, dysplastic ears,
hypotonia, and speech delay [Figure 6A, Supplementary Figures 4 and 5].

Consistent with these findings, de novo, deleterious PBX1 sequence variants result in a highly variable
syndromic form of intellectual disability, which includes external ear abnormalities and congenital
defects of the kidney and urinary tract. In fact, most patients with 1q deletion including PBX1 have
renal abnormalities and the association between Cakut syndrome and PBX1 variants/deletions is well
demonstrated [15,16] . PBX1 alterations may also contribute to severe behavioral traits such as autism and
[15]
obsessive-compulsive disorder . Indeed, in addition to moderate ID, the phenotype of our Case 1 was
characterized by repetitive movements and psychiatric traits resembling Tourette syndrome, such as
obsessive-compulsive behavior with episodes of coprolalia and soliloquy [Table 1]. Interestingly, PBX1
gene has been recently identified among pleiotropic risk loci that play important roles in the neurological
[17]
development processes associated with psychiatric disorders .
We also identified a 1.9-Mb genomic region (168,556,004-170,516,641) showing a high cumulative
probability for microcephaly, brachydactyly, and short hands and feet [Figures 5 (N.2) and 6A (N.2)].

Within this region, the ATP1B1 gene [Figure 6C] shows the highest pLI value with observed/predicted
scores indicating haploinsufficiency intolerance [Supplementary Table 3]. ATP1B1 (OMIM 182330) encodes
for the subunit ß1 of Na,K-ATPase family, responsible for the homeostasis of the electrochemical gradients
of Na and K ions across the plasma membrane. While mutations of the of Na,K-ATPase α-subunits have
already been associated with neurological diseases (reviewed by Clausen et al. ), no confirmed mutations
[18]
in any of the ß-subunits have yet been correlated with human disorders. Interestingly, ATP1B1, as part
of an Na,K-ATPase multiprotein complex, interacts with the calcium channel TRPV4 (MIM *605427)
[19]
whose heterozygous de novo variants, either or missense, associate with skeletal disorders. Similar to our
patients (Cases 2 and 3), those with TRPV4-related skeletal dysplasias include short stature, small hands
and feet, and brachydactyly [20-22] , suggesting a role for ATP1B1 in these disorders.

Deletions within SRO-I (chr1:172,460,683-172,281,412) show high probability to include a disease-locus for
[2]
ID, microcephaly, and, as previously defined by Lefroy , skeletal anomalies including short hands and feet
and brachydactyly [Figures 5 and 6A].

Specifically, the SRO-I includes Dynamin-3 (DNM3, OMIM *611445), a gene harboring a 7.9-kb antisense
transcript for miR199-214 genes . These two miRs are involved in vertebrate skeletogenesis [24,25] , thus
[23]
[2,6]
suggesting a role for the skeletal phenotype in 1q24 deleted patients . Indeed, the phenotype of Cases
2-4 with 1q24q25 deletions fully including the DNM3, with its two guests miR199-214 [Figure 6D], share
significant pre- and postnatal growth deficiency, microcephaly, and small hand and feet with fifth finger