Introduction
Pathogenic copy number variants (pCNVs) of interstitial or terminal deletions in the
long arm of chromosome 6 are rare cytogenomic abnormalities detected in approximately
0.05% of patients with intellectual disability (ID) and developmental delay (DD).[1 ] Earlier studies suggested simple terminal deletions of 6q as an emerging new syndrome.[2 ]
[3 ] Further studies using chromosome analysis, fluorescence in situ hybridization (FISH),
and array comparative hybridization (aCGH) calibrated various sizes from patients
with 6q deletions and constructed a phenotypic map for deletions of 6q.[4 ]
[5 ]
[6 ]
[7 ] A systematic review of patients with deletions of 6q summarized the phenotypic features
from 28 cases and presented a deletion map from 13 cases.[8 ] This map showed an association of deletions of 6q23-q25 with limb defect and cleft
palate, deletions of 6q26-q27 with cardiac defects, genital hypoplasia, short neck,
and retinal abnormalities, and subtelomeric or terminal deletions of 6q with ID, DD,
dysmorphic features, brain anomalies, seizure, hydrocephalus, microcephaly, growth
retardation, and vertebral anomalies.
In the past decade, the application of high-resolution aCGH has allowed more accurate
detection of genomic coordinates and gene content from pCNVs and, thus, significantly
improved the diagnostic accuracy and efficacy.[9 ]
[10 ]
[11 ] Here, we presented the clinical features and cytogenomic results from eight unrelated
patients with different deletions at the 6q26-q27 region. We also performed a literature
review to evaluate the clinical and cytogenomic findings from 28 patients with a deletion
of 6q26-q27.[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] From this series of 36 patients, we defined genotype–phenotype correlations from
prenatal to postnatal stages and two critical regions with putative haploinsufficient
genes and other candidate morbid genes. These results provided evidence for diagnostic
interpretation, genetic counseling, and clinical management of patients with deletions
of 6q26-q27.
Materials and Methods
Human Subjects
Eight patients with a deletion of 6q26-q27 were diagnosed at the Yale Clinical Cytogenetics
Laboratory by G-band karyotyping, FISH, and aCGH. Clinical information from the initial
diagnosis to follow-up visits was evaluated. This project was categorized as a chart
review retrospective case study and deemed exempt from Institutional Review Board
(IRB) approval and granted waiver of consent based on the policy of the Yale University
IRB.
Karyotyping, FISH, and aCGH Analysis
Karyotyping was performed on G-band metaphases of cultured lymphocytes from peripheral
blood specimens following the laboratory's standard protocols. Genomic DNA was extracted
from peripheral blood lymphocytes using the Gentra Puregene Kit (Qiagen, Valencia,
CA, United States). FISH tests were performed on metaphase cells using a DNA probe
specific for the chromosome 6q terminal region (Abbott Inc. Des Plaines, IL, United
States). aCGH was performed using Agilent SurePrint G3 Human CGH + SNP microarray
(Agilent Technologies, Inc., Santa Clara, CA, United States) as previously described.[9 ]
[10 ] The base pair designation for detected pCNVs was based on the February 2009 Assembly
of human genome (GRCh37/hg19).
Literature Review and Data Analysis
A systematic literature review was performed for case reports with deletions of 6q26-q27
from 2010 to 2020 from PubMed using the following keywords: subtelomeric 6q deletion,
6q terminal deletion, FISH, aCGH, 6q26, 6q27, 6q26-qter, and deletion. Only patients
with an isolated deletion of 6q26-q27 were selected. Familial cases with multiple
affected patients were counted as one by the proband. This literature search found
14 articles with 28 patients having a deletion of 6q26-q27.[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] Reported patients without cytogenomic mapping for the deletion, with large deletions
extending to 6q25, and compound rearrangements involving other chromosomes were excluded.[26 ]
[27 ]
Genotype–phenotype correlations were evaluated from prenatal to postnatal stages by
assessing the percentage of patients with major clinical findings (>50%) and minor
symptoms (<50%). The classification of the clinical significance of terminal and interstitial
deletions follows the technical standards of the American College of Medical Genetics
and Genomics (ACMG) by a quantitative and evidence-based scoring.[28 ] Critical regions were constructed by the smallest overlapped deletions or specified
fragile sites with potential candidate genes. Online Mendelian Inheritance in Man
(OMIM) morbid genes (https://www.omim.org/ ) and putative haploinsufficient genes by DECIPHER haploinsufficiency index (%HI)
were selected from ClinGen using the dosage sensitivity filter for 6q26-q27 region.
Results
Clinical and Cytogenomic Findings from the 36 Patients
As shown in [Table 1 ], 36 patients and their clinical features were arranged numerically at the prenatal,
perinatal, infant, pediatric, and adult stages. The clinical features and cytogenomic
results of eight patients with a deletion of 6q26-q27 from Yale Clinical Cytogenetics
Laboratory were described as follows.
Table 1
The clinical features of 36 patients with deletions of 6q26-q27
Development stages
Pts (# in Ref)
Sex (age range)
Inheritance
Size (Mb)
DD/ID
Structural brain abnormality
Facial dysmorphism
Hypotonia
Learning difficulty or language delay
Seizures
Vertebral or spinal cord malformation
Hydro- cephalus
Micro- cephaly
Joint laxity
Others
Prenatal
1 (2)
F(21 gw–TOP)
dn
9.9
+
–
2
F(22 gw)
mat
0.38
+
+
3
F(29 gw–nb)
dn
4.9
+
4
M(30 gw–sb)
dn
4.6
+
+
+
HK
Perinatal
5
M(20 gw–21 d)
–
0.24
+
+
+
+
+
MDKH
6 (10)
F(20 gw–1.5 y)
pat
1.5
+
+
+
–
–
7 (2)
F(22 gw–5m)
pat
2
+
–
–
8 (1)
M(32 gw–2y)
mat
3.9
+
+
+
+
+
–
–
+
9 (12)
M(pn–6 y)
mat
1.2
+
+
+
+
+
Prenatal
100%
Infant
10 (4)
F(nb)
dn
2.2
+
+
11 (6)
F(nb)
dn
2.2
+
+
–
+
+
+
–
+
–
–
12 (TS1)
M(2 m)
–
8.93
+
+
+
+
+
+
ADHD, ASD, HL
13 (3)
F(4 m)
dn
8.1
+
+
+
+
+
+
–
macro
–
Pediatric
14
F(4 m–8 y)
dn
5.7
+
+
+
+
+
+
EDS
15 (5)
F(8 m)
dn
5.65
+
+
+
+
+
+
+
macro
16 (TS2)
M(y)
dn
7.95
+
+
+
+
17(TS3)
F(2 y)
dn
1.09
+
+
+
Toe-walking, autism
18 [7]
F(2.5 y)
–
1.75
+
+
+
+
+
–
–
–
–
–
19
M[6 y]
dn
8
+
+
+
–
+
–
–
+
20 [4]
F(6 y)
–
6.2
+
+
+
+
+
–
+
–
+
–
21(TS4)
M(6 y)
p/m
0.08
+
+
+
+
Scoliosis
22 (5)
F(7 y)
–
6
+
+
+
+
+
+
+
23 (TS5)
M(8 y)
dn
5.24
+
+
+
+
IA, VSD, PDA, OCD, ADHD
24 (TS6)
M(8 y)
–
0.99
+
25 (TS7)
(9 y)
–
9.50
+
+
+
+
+
+
Poor vision
26
F(3–12 y)
mat
0.33
+
+
+
+
+
–
+
+
27 (2)
M(12.5y)
–
7
+
+
+
+
+
–
+
28 (3)
M(13 y)
–
7
+
+
+
+
+
–
+
29 (6)
M(15 y)
–
3
+
+
+
+
–
–
–
+
30 (1)
F(17 y)
–
2.15
+
+
+
+
+
–
–
31 (8)
M(18 y)
–
2
+
+
+
+
+
+
Adult
32 (TS8)
F(23 y)
dn
6.61
+
+
+
+
+
VSD, PDA, CD, EP
33 (4)
M(25 y)
–
6
+
+
+
+
+
+
34 (2)
M(25 y)
dn
5.21
–
–
–
–
–
–
–
+
–
Anosmia
35 (7)
M(33 y)
–
2.5
+
+
+
+
+
36
M(29 y)
pat
0.38
EOPD
Postnatal
81%
72%
66%
63%
50%
47%
31%
22%
22%
19%
Abbreviations: –, not present; +, present; ADHD, attention deficit hyperactivity disorder;
ASD, autism spectrum disorder; CD, ciliary dyskinesia; DD, Development delay; dn,
de novo; EDS, Ehlers-Danlos syndrome; EOPD, early-onset Parkinson disease; EP, episodes
of psychosis; gw, gestational weeks; HK, horseshoe kidney; HL, hearing loss; IA, imperforate
anus; ID, Intellectual disability; mac, macrocephaly; mat, maternal; MDKH, multicystic
dysplastic kidney and hydronephrosis; nb, newborn; OCD, obsessive-compulsive disorder;
p/m, bi-parental; pat, paternal; PDA, patent ductus arteriosus; sb, stillbirth; top,
termination of pregnancy; VSD, ventricular septal defect.
Note: Patients (Pts) were collected from this study (TS) and published reports, and
number in parenthesis () refers to the patient number in TS and the reports; patients
1, 11, 13, 15, 18, and 20 were from the report of Peddibhotla et al (2015),[20 ] patient 2 was from Thakur et al (2018),[22 ] patient 3 was from Li et al (2011),[17 ] patient 4 was from Valduga et al (2010),[13 ] patient 5 was from Puvabanditsin et al (2020),[25 ] patients 6, 9, 22, 27, 28, 29, 31, 33, and 35 were from Conti et al (2013),[19 ] patients 7 and 8 were from Wadt et al (2012),[18 ] patient 10 was from Dupé et al (2011),[15 ] patient 14 was from Mosca et al (2010),[12 ] patient 19 was from De Cinque et al (2017),[21 ] patient 26 was from Hanna et al (2019),[24 ] patient 30 was from Rigon et al (2011),[14 ] patient 34 was from Gerber et al (2011),[16 ] and patient 36 was from Williams et al (2018).[23 ]
Patient One (Listed as Patient 12 in [Table 1 ])
A male newborn was referred for cytogenomic tests with clinical indications of microcephaly
and hearing loss. The karyotype showed a terminal deletion at 6q26, denoted as 46,XY,del(6)(q26).
aCGH defined an 8.930 Mb deletion at 6q26q27 (chr6:161981583_170911240) including
36 genes from PRKN (PARK2 ) to PDCD2 . From the age of 2 years to the present age of 20 years, follow-up examinations on
the patient noted central hypotonia, peripheral hypertonia, DD/ID involving both motor
and speech development, seizures, attention-deficit and hyperactivity disorder (ADHD),
autism spectrum disorder (ASD), cognitive limitation, and abnormal brain MRI.
Patient Two (16)
A 1-year-old boy was noted with microcephaly, DD, and seizures. The karyotype showed
a terminal deletion at 6q26, denoted as 46,XY,del(6)(q26)dn. FISH test using subtelomeric
probes for the 6p and 6q loci confirmed the terminal deletion of 6q. aCGH defined
an 8.031 Mb deletion of 6q26q27 (chr6:162983518_171014790) including 36 genes from
PRKN to PDCD2 ([Fig. 1A ]). He sat at 6 months, crawled at 13 months, pull to stand at 16 months, and took
steps at 24 months. He had a significant delay in both receptive and expressive language
and could say a few single words and phrases at the age of 3 years. Follow-up clinical
examination up to the age of 14 years noted microcephaly, cognitive impairment, and
presumably symptomatic focal impaired seizures with occasional secondary generalization.
He had two surgeries to correct strabismus. Electroencephalogram performed at 9-year-old
showed marked slowing over the left hemisphere and occasional left temporal sharp
waves. He had been seizure-free since starting Lamictal at the age of 10 years. He
was in a special education class. Chromosome analyses on both parents found normal
results, indicating a de novo deletion of 6q in the affected boy.
Fig. 1 Cytogenomic results for two patients with a deletion of 6q26-q27. (A ) An 8.031 Mb deletion at 6q26 in patient two (from left to right images of chromosome,
FISH, and aCGH), and (B ) A 9.577 Mb deletion at 6q26 in patient seven.
Patient Three (17)
A 2-year-old female had global DD, hypotonia, language impairment, toe-walking, and
behavioral concerns for autism disorders. The karyotype showed a normal female karyotype,
and aCGH detected a 1.089 Mb deletion at 6q27 (chr6:169818238_170906796, including
nine genes WDR27 , PHF10 , TCTE3 , EMARD [C6orf70 ], DLL1 , FAM120B , PSMB1 , TBP , and PDCD2 ). Follow-up aCGH analysis on both parents found normal results, indicating a de novo
deletion of 6q27.
Patient Four (21)
A 6-year-old male showed global DD, speech delay, minor dysmorphic features, and scoliosis.
aCGH detected an 81 kb bi-allelic deletion at 6q26 (chr6:162198305_162279506), including
intron 4, exon 5, and intron 5 of the PRKN gene and regions of homozygosity in 1.3% of the genome. Follow-up analysis on the
parents found both mother and father as heterozygous carriers for this deletion. Family
history showed first cousin consanguinity in the parents.
Patient Five (23)
Chromosome analysis on an 8-year-old boy detected a terminal deletion at 6q27, denoted
as 46,XY,del(6)(q27)dn. aCGH defined a 5.244 Mb deletion at 6q27 (chr6:165667663_170911240)
including 33 genes from C6orf118 to PDCD2 . This preterm newborn baby had an imperforate anus, which was repaired after birth.
The boy was followed up from the ages of 6 to 8 years with seizures, myelomeningocele,
spinal bifida, urinary incontinence, ID, obsessive-compulsive disorder (OCD), ADHD,
and sleep disturbance. He also had ventricular septal defect (VSD), patent ductus
arteriosus (PDA), and tethered cord with filum terminale lipoma with conus at L2 and
L3 levels, and MRI findings concerned for occult dysraphism at S1/S2. Chromosome and
aCGH analyses on both parents found normal results, indicating a de novo deletion
of 6q in the affected boy.
Patient Six (24)
The karyotype on an 8-year-old boy with DD showed a normal male pattern and aCGH detected
a 0.985 Mb deletion involving three genes PRKN (PARK2 ), PACRG , and QKI at 6q26 (chr6:162870169_163855503) with breakpoints at intron 1 of the PRKN and QKI genes.
Patient Seven (25)
A 9-year-old girl was noted with ID, epilepsy, microcephaly, and poor vision with
corrective lenses. The karyotype showed a terminal deletion at 6q26, denoted as 46,XX,del(6)(q26).
FISH test using subtelomeric probes for the 6p and 6q loci confirmed the terminal
deletion of 6q, and aCGH defined a 9.577 Mb deletion of 6q26q27 (chr6:161437468_171014790)
including 38 genes from MAP3K4 to PDCD2 ([Fig. 1B ]). This patient showed congenital hydrocephalus at birth and had undergone ventriculoperitoneal
shunt and endoscope. She had developmental and speech delays. She had a history of
seizures and had been seizure-free on phenobarbital. The girl had early pubertal development
including secondary sexual characteristics at the age of 11 years. She had difficulty
in learning and language expression and received special education. She could read
letters and numbers and did simple arithmetic but could not read at the age of 13
years. She received Depokote to control bleeding during menses since the age of 17
years. Follow-up clinical examinations up to the age of 21 years noted kyphoscoliosis
and menorrhagia.
Patient Eight (32)
A 23-year-old female had seizure disorder and ID (IQ < 70). She was also known to
have anxiety disorder with episodes of psychosis and ciliary dyskinesia with frequent
pulmonary infections. Other clinical findings included strabismus, gastroesophageal
reflux, hypotonia, VSD, and PDA which resolved spontaneously. The karyotype showed
a terminal deletion at 6q26, denoted as 46,XX,del(6)(q26)dn. aCGH detected a 6.608 Mb
deletion at 6q26q27 (chr6:164312707_170921089) including 33 genes from C6orf118 to PDCD2 . Both parents had chromosome analysis done with normal results.
Clinical Findings for Deletions of 6q26-q27
Of these 36 patients with deletions of 6q26-q27 ([Table 1 ]), 18 were male and 18 were female; 29 patients (81%) had a terminal deletion, whereas
seven patients (19%) had a proximal or distal interstitial deletion. Of the 22 patients
with follow-up parental studies, 14 (64%) were de novo, four (18%) were maternally
inherited, three (14%) were paternal, and one (4%) was inherited from both parents.
Cytogenomic and clinical findings grouped into prenatal, perinatal, infant, pediatric,
and adult stages are summarized in [Fig. 2 ] and [Table 1 ]. All four prenatal patients and five perinatal patients showed brain abnormalities
(100%, nine out of nine) by ultrasound examination. The major postnatal clinical features
observed in the five perinatal and 27 postnatal patients were DD/ID (81%, 26 out of
32), brain abnormalities (72%, 23 out of 32), facial dysmorphism (66%, 21 out of 32),
hypotonia (63%, 20 out of 32), learning difficulty or language delay (50%, 16 out
of 32), and seizure (47%, 15 out of 32). Other clinical features included vertebral
or spinal cord malformation (31%, 10 out of 32), microcephaly (22%, 7 out of 32),
hydrocephalus (22%, 7 out of 32), joint laxity (19%, 6 out of 32), VSD, ADHD, and
ASD (6%, 2 out of 32), as well as hearing loss, poor vision, and early-onset Parkinson
disease (EOPD) (3%, 1 out of 32).
Fig. 2 Cytogenomic mapping of critical regions and genotype–phenotype correlations for morbid
genes of 6q26-q27. A cytogenomic map for sizes of deletions, critical regions, and
candidate genes of 6q26-q27. The upper panel shows the chromosome 6q26-q27 region
with a genomic coordinate. The middle panel shows the size and location of the 36
deletions following prenatal to postnatal stages (each red bar for a deletion and
numbering on the right side matches patient number in [Table 1 ]). The lower panel shows critical regions (CR), morbid genes (putative haploinsufficient
genes in red), and genotype–phenotype correlations for morbid genes in the 6q26-q27
region.
Critical Regions and Genotype–Phenotype Correlations within 6q26-q27
Four patients with a small distal interstitial deletion (patients 6, 9, 17, and 31
in [Table 1 ]) were mapped critical region 1 (CR1) spanning 1.1 Mb, which encompassed the WDR27 , PHF10 , TCTE3 , ERMARD , DLL1 , FAM120B , PSMB1 , TBP , and PDCD2 genes.[19 ] The CR1 contained haploinsufficient genes for deletions of 6q27. Four proximal interstitial
deletions at 6q26 involving the PRKN gene were noted in two patients with DD, a preterm neonate, and an adult with EOPD
(patients 5, 21, 24, and 36 in [Table 1 ]).[23 ]
[25 ] Following the ACMG guidelines for CNV classification, these interstitial deletions
were scored 0.15 to 0.3 and were considered as a variant of uncertain significance
(VUS).[28 ] Excluding pseudogenes, there were 53 coding genes in the 6q26-q27 region. Of them,
11 OMIM morbid genes LPA , PLG , PRKN , PDE10A , MPC1 , RNASET2 , SMOC2 , THBS2 , ERMARD , DLL1 , and TBP , three putative haploinsufficient genes PRKN , QKI , and TBP (by DECIPHER HI index <10%), and one haploinsufficient gene DLL1 (by HI score and HI index in ClinGen) were listed as candidate genes. The fragile
site at 6q26, FRA6E, spanned approximately 3.6 Mb (chr6:160000000_163600000).[29 ] This region, containing the putative haploinsufficient gene PRKN and breakpoints of four interstitial and six terminal deletions, was defined as critical
region 2 (CR2). These two critical regions with known morbid and haploinsufficient
genes of 6q26-q27 and genotype-phenotype correlations are shown in [Fig. 2 ].
Discussion
From the 36 patients with a deletion of 6q26-q27, the equal ratio of male versus female
(50 vs. 50%) showed no gender difference. Approximately, two-thirds of these 6q deletions
were de novo and one-third were inherited, indicating that a significant portion was
familial; thus, follow-up parental study was recommended. Patients with a deletion
at 6q27 showed scattered breakpoints with different sizes and the lack of recurrent
deletions. The lack of clusters of segmental duplications or low copy repeats at 6q26-q27
region was noted from the Human Genome Browser (http://genome.ucsc.edu/ ) and likely explained the absence of recurrent deletions caused by non-allelic homologous
recombination. Therefore, the deletion formation mechanism most likely involved the
repair of subtelomeric double-strand breaks at 6q27. However, the breakpoints at 6q26
fell in the FRA6E site and suggested a “hotspot” for interstitial and terminal deletions.[29 ] Further, sequence analysis of breakpoints at 6q26 could define the underlying mechanism
of these deletions and their relations to the FRA6E site.
A recent retrospective analysis of cytogenomic abnormalities detected by aCGH showed
a detection rate of subtelomeric pCNVs in 1% of pediatric patients and 0.5% of prenatal
cases.[11 ] For the 36 patients with a deletion of 6q26-q27, nine were detected prenatally,
22 were detected in infancy and childhood, and five were detected in adulthood. These
results indicated that over two-thirds of patients were detected postnatally with
variability in onset and severity of diseases. Of the nine fetuses detected prenatally,
termination of pregnancy was decided for a fetus with a 9.9 Mb deletion, stillbirth
was noted in a fetus with a 4.6 Mb deletion, and the remaining fetuses had deletions
in the size ranging from 0.38 to 4.9 Mb. These observations suggested an increased
risk of stillbirth for terminal deletions of 6q in prenatal diagnosis.
An approach combining cytogenomic mapping and bioinformatic mining has been used to
define critical regions and interacting candidate genes for ID.[30 ] The collection of more patients and the curated databases with improved bioinformatic
tools enabled precise genotype–phenotype correlations and fine mapping of critical
regions with haploinsufficient genes. The CR1 at 6q27 contained three morbid genes
ERMARD (OMIM615544), DLL1 (OMIM618709), and TBP (OMIM607136), and the last two were haploinsufficient. The clinical findings from
two patients (patients 2 and 26 in [Table 1 ]) with a smaller deletion including the DLL1 and TBP genes but not the ERMARD gene indicated that haploinsufficiency of these two genes is sufficient to cause
the 6q terminal deletion syndrome.[22 ]
[24 ] Recent exome sequencing in patients with neurodevelopmental disorders identified
heterozygous pathogenic variants in the DLL1 gene in 12 unrelated families; the most common clinical features for these patients
were ID, ASD, seizures, variable brain malformations, muscular hypotonia, and scoliosis.[31 ] Similar clinical features were noted in patients with a deletion involving the CR1
at 6q27. These clinical and genetic findings support haploinsufficiency of the DLL1 gene as a mechanism for the pathogenesis of the 6q terminal deletion syndrome. The
DLL1 gene encodes a human homolog of a Notch Delta ligand involved in cell adhesion, cell
communication and fate determination, and Notch pathway of biological processes. The
DLL1 protein played a major role in the nervous system of paraxial mesoderm during somitogenesis;
mice with DLL1 deletion showed severe nervous system defects in embryogenesis.[15 ]
[32 ]
The TBP gene encodes a TATA-binding protein involved in the initiation of transcription by
forming transcription complex TFIID associated with TBP-associated factors. This transcription
complex regulates many biological processes of neurodevelopment disorders. The CAG
repeat expansion in the N-terminal domain of TBP causes late-onset spinocerebellar ataxia.[33 ] One patient analyzed by BAC clone FISH showed a smaller terminal deletion of approximately
400 kb involving only the PSMB1 , PDCD2, and TBP genes.[4 ] The study of heterozygous TBP mice suggested that TBP is potentially involved in cognitive development.[7 ] A functional study noted that the silencing of ERMARD in the developing rat neocortex produced periventricular nodular heterotopia.[14 ] These results implied modifying effects from the TBP and ERMARD genes for the 6q terminal deletion syndrome. Additionally, intra-family variability
was noted in a phenotypically normal carrier mother with a terminal deletion of 0.6
to 0.8 Mb at 6q27 and two pregnancies of a malformed fetus.[34 ] Furthermore, large deletions extending to 6q25, compound rearrangements involving
6q27 and other chromosomes, and ring chromosome 6 involving a deletion of 6q27 also
present clinical features of the 6q terminal syndrome.[26 ]
[27 ]
[35 ]
The PRKN gene encodes a RING domain-containing E3 ubiquitin ligase involved in proteasome-dependent
degradation of proteins, and pathogenic variants in the gene are known to cause Parkinson's
disease (OMIM600116). A 381 kb deletion including exons 1 and 2 of the PRKN gene was transmitted from an unaffected father to his son; an additional de novo
71 kb deletion in trans involving exon 3 of the PRKN gene in the son likely contributed to the EOPD with the onset of disease at the age
of 20 years.[23 ] CNVs affecting different exons 2 to 7 of the PKRN gene have been found in familial cases with asymptomatic carriers, high-function
autism, and ASD.[36 ] A recent study indicated a significant association of short deletions near the PRKN gene with a major depressive disorder (MDD).[37 ] These studies indicated the associations of intra-genic PRKN deletions with EOPD, ASD, and MDD. Even though small deletions involving the PRKN gene are most likely classified as VUS by current technical standards, clinical re-evaluation
of psychologic and behavior disorders in follow-up visits and laboratory re-analysis
of the deletion and its impact on gene function should be considered. A patient with
clinical features of the 6q terminal deletion was detected with a reciprocal balanced
translocation, t(5;6)(q23.1;q26); the breakpoint at 6q26 disrupted the QKI gene and decreased its expression.[38 ] The QKI gene belongs to a family of RNA-binding protein with an HNRNPK homology and KH domain,
which regulates RNA splicing, export of target RNAs from nucleus, translation of proteins,
and RNA stability; its regional specificity to target genes in the human prefrontal
cortex and hippocampus has made it a candidate gene for schizophrenia.[39 ] The clinical significance for CR2 requires further investigation from more patients
with deletions involving the PRKN and QKI genes.
