. 2016 Oct 13;99(5):1015–1033. doi: 10.1016/j.ajhg.2016.08.022

Table 5.

DGAP259: Significant Protein-Coding Genes Surrounding the Breakpoints according to TADs and Convergent Genomic Evidence

Gene	Nucleotides (GRCh37/hg19)	Description	OMIM^³⁷	OMIM Morbid^³⁷	DDG2P^³⁹	HI (%)^³⁶	Notes
3p26.3 Breakpoints on Rearrangement_D (1,408,99{6}) and Rearrangement_G (1,408,984)

CNTN6 (disrupted)	1,134,260–1,445,901	contactin 6	607220	−	−	39.69	no reported phenotype association; neural adhesion molecule^⁴⁸
CNTN4	2,140,497–3,099,645	contactin 4	607280	−	−	6.9	disrupted in a subject with a 3p deletion syndrome (autosomal-dominant) phenotype^⁴⁹ (cerebral and renal malformation phenotype of DGAP259)

3p26.3 Breakpoints on Rearrangement_D (1,408,99{6}) and Rearrangement_G (1,408,984)

TBC1D5 (disrupted)	17,198,654–18,486,309	TBC1 domain family member 5	615740	−	−	5.84	no reported phenotype association
SATB1^a	18,386,879–18,487,080	SATB homeobox 1	602075	−	−	2.15	global genome organizer⁵⁰, ⁵¹ (complex chromosomal rearrangement of DGAP259); role in neuronal plasticity of cortical neurons and regulation of key neuronal genes⁵², ⁵³ (cerebral malformation phenotype of DGAP259)

5q14.3 Breakpoints on Rearrangement_B (88,756,2{48-56}) and Rearrangement_E (88,756,2{39-40})

MEF2C	88,013,975–88,199,922	myocyte enhancer factor 2C	600662	+	+	0.26	haploinsufficiency (autosomal dominant, monoallelic) associated with mental retardation, stereotypic movements, epilepsy, and cerebral malformations (MIM: 613443)⁴⁷, ⁵⁴ (cerebral malformation and hypoplastic corpus callosum phenotype of DGAP259); role in synaptic plasticity and hippocampal-dependent learning and memory^⁵⁵ (9p23 breakpoints of DGAP259 disrupt PTPRD1 with similar role)
CETN3	89,688,078–89,705,603	centrin 3	602907	−	−	5.94	present in centrosomes and important role in early cleavage of frog embryos^⁵⁶ (complex chromosomal rearrangement of DGAP259)

7q35 Breakpoints on Rearrangement_B (147,718,91{1-9}) and Rearrangement_E (147,718,90{7-8})

CNTNAP2 (disrupted)	145,813,453–148,118,090	contactin associated protein-like 2	604569	+	+	4.94	susceptibility to autism type 15;^⁵⁷ homozygous or compound-heterozygous mutations cause Pitt-Hopkins-like syndrome 1 (MIM: 610042)^⁵⁸ (cerebral malformation phenotype of DGAP259; 18q21 breakpoints are one TAD downstream of TCF4, associated with Pitt-Hopkins syndrome)
CUL1^a	148,395,006–148,498,128	cullin 1	603134	−	−	4.3	regulates the mammalian G1/S transition^⁵⁹
EZH2^a	148,504,475–148,581,413	enhancer of zeste 2 polycomb repressive complex 2 subunit	601573	+	+	3.07	has a critical role during normal and perturbed development of the hematopoietic and central nervous systems,^⁶⁰ maintains homeotic gene repression, and is thought to control gene expression by regulating chromatin^⁶¹ (cerebral malformation and complex chromosomal rearrangement of DGAP259)

7q36.3 Breakpoints on Rearrangement_A (155,701,797) and Rearrangement_C (155,700,873)

SHH	155,592,680–155,604,967	sonic hedgehog	600725	+	+	0.66	haploinsufficiency (autosomal dominant, monoallelic) associated with HPE3,^⁶² which has a long-range regulation-associated phenotype^⁶³ (cerebral malformation phenotype of DGAP259)

9p23 Breakpoints on Rearrangement_F (9,646,47{5}) and Rearrangement_I (9,646,471)

PTPRD (disrupted)	8,314,246–10,612,723	protein tyrosine phosphatase, receptor type D	601598	−	−	0.14	homozygous microdeletion causes trigonocephaly, hearing loss, and intellectual disability, which overlap the autosomal-dominant 9p deletion syndrome^⁶⁴ (cerebral malformation phenotype of DGAP259); role in synaptic plasticity and hippocampal-dependent learning and memory^⁶⁵ (5q14.3 breakpoints are within the same TAD as MEF2C with similar role)

18p11.31 Breakpoints on Rearrangement_D (6,375,05{1}), Rearrangement_G (6,559,611), and Rearrangement_H (6,375,0{52-48} and 6,559,{598-602})

L3MBTL4 (disrupted)	5,954,705–6,415,236	L(3)Mbt-like 4 (Drosophila)	−	−	−	59.07	no reported phenotype association

18q21.3 Breakpoints on Rearrangement_F (54,660,13{8}) and Rearrangement_I (54,660,136)

TCF4^a	52,889,562–53,332,018	transcription factor 4	602272	+	+	0.38	haploinsufficiency (autosomal dominant, monoallelic) is associated with Pitt-Hopkins syndrome^⁶⁶ (cerebral malformation phenotype of DGAP259, 7q35 breakpoints disrupt CNTNAP2, related to Pitt-Hopkins-like syndrome^⁵⁸)
WDR7 (disrupted)	54,318,574–54,698,828	WD repeat domain 7	613473	−	−	14.85	no reported phenotype association; localized to synaptic vesicles in rat and mouse brain^⁶⁷
NEDD4L^a	55,711,599–56,068,772	neural precursor cell expressed, developmentally down-regulated 4-like, E3 ubiquitin protein ligase	606384	−	−	8.66	regulator of renal sodium channels; involved in induction of mesoendodermal fates in mouse embryonic stem cells^⁶⁸ (renal malformation phenotype of DGAP259)

Abbreviations are as follows: DDG2P, Developmental Disorders Genotype-to-Phenotype database; HI, haploinsufficiency index; and HPD3, holoprosencephaly type 3.

Although not located within the same hESC TAD^¹⁸ as the breakpoint, these genes might be relevant to the phenotype of DGAP259 given the complexity of the rearrangement.