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European Journal of Animal Genetics (2010) 18, 1302–1309; doi:10.1038/ejhg.2010.115; appear online 21 July 2010
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Maria C Bonaglia1, Susan Marelli2, Francesca Novara3, Simona Commodaro1, Renato Borgatti2, Grazia Minardo4, Luigi Memo4, Elisabeth Mangold5, Silvana Beri6, Claudio Zucca7, Daniele Brambilla8, Massimo Molteni9, Roberto Giorda6, Ruthild G Weber5 and Orsetta Zuffardi3,10
De novo microdeletions detected by genome-wide arrangement assay at 19p13 accept been appear in few patients,1, 2, 3, 4, 5 all of whom had malformations and brainy amentia (MR). We present the abundant analytic and atomic description of two new cases (cases 1 and 3) with partially overlapping 19p13 microdeletions articular by investigating patients with syndromic MR application arrangement allusive genomic admixture (aCGH). We additionally re-analyzed at college resolution and acquired the analytic aftereffect of one appear case1 (case 2) with a cryptic 19p13.12 abatement absolutely overlapping that of case 1. The beeline arena of overlap (SRO) amid the three cases is 359 kb in admeasurement and contains applicant genes potentially amenable for their accepted phenotypic appearance (psychomotor, mental, accent adjournment and sensorineural audition loss). Genes alfresco the SRO are additionally discussed.
All patients are declared in detail in the area below. The analytic appearance of our capacity and of patients with overlapping 19p13.12 deletions appear by Jensen et al,2 Lysy et al,4 and Auvin et al5 are abbreviated in Table 1.
The proband is a male, the added adolescent of advantageous non-consanguineous parents age-old 31 (mother) and 36 years (father) at his bearing (Figure 1). Commitment was at 36 weeks of evolution by cesarean section. Bearing weight was 2400 g (3–10th centile), and OFC was 32 cm (3–10th centile). Breadth and APGAR arrangement were not available. At birth, some dysmorphic appearance were noted: aberrant ears, submucous broken palate, mutual cutaneous syndactyly of fingers II and III and toes and hypospadias. A accepted karyotype was performed with accustomed results.
Photographs of case 1 at the age of 6 months (a), 8 years (b) and 17 years (c), and aboveboard (d) and crabbed (e) appearance at the age of 31 years. Note the brachycephaly (a, d, e), alpine forehead (a, c, d), ptosis (a–c), anteverted adenoids (a–d), continued philtrum (a–d), attenuate aerial lip (a–e), synophrys (a–d), abbreviate close (c), anteverted aerial (a, c, d) with attenuate helices (e) as able-bodied as symmetrically arranged, vaguely categorical nodules and partly allied plaques accompanied by a down-covered erythema on the forehead at age 31 years (d, e).
Early motor milestones were acutely delayed: he acquired arch ascendancy at 2 years and was able to airing afterwards abutment at 3 years. He showed abstinent MR and accent delay. Hyperactivity was additionally observed.
At the age of 11 years, a assay of praecox boyhood was made. Cardiac ultrasound showed balmy aortic and mitral valve regurgitation. Academician CT scans were normal. During adolescence, repetitive and banal behavior worsened, with accepted questions and actual bound interests. He developed adverse behavior as a acknowledgment to basal ecology changes, with auto-aggressive and sometimes hetero-aggressive acting out. A assay of overactive anarchy associated with MR and banal movements (ICD 10) was fabricated and specific biologic assay (clomipramine, chlorpromazine and fluvoxamine) was started with accelerating improvement.
At 24 years, the accommodating showed several ambiguous clonic seizures with avalanche afterwards an access in the fluvoxamine dosage. Admitting its abeyant pro-convulsive effects, antipsychotic assay could not be cone-shaped and antiepileptic abiding assay was started with sodium valproate. Complete access ascendancy was accomplished with a aftereffect aeon of 8 years. EEG recordings showed a all-around slowing of accomplishments action afterwards epileptiform abnormalities.
At the age of 27 years, Auditory Academician Middle Latency Responses (ABR and MLR) and Behavioral Audiometry (VRA) exams appear mutual sensorineural audition loss. The abstracts acquired by authentic accent audiometry (500–1000 and 2000 Hz) were 65 dBHL (right ear) and 80 dBHL (left ear). Tympanometry after-effects were accustomed in the appropriate ear, admitting the larboard ear was classified as blazon B, according to the allocation of Jerger.6 Mutual over-the-ear audition aids were positioned. Over aftereffect aeon of 4 years, the bearings has remained stable. Scoliosis was additionally present at this age.
At the patient's aftermost analytic appraisal (31 years), the afterward appearance were observed: abbreviate ability (height 150 cm; −3 SD), ample (83 kg: BMI of 36.4 kg/m2; 3 SD), and a about baby arch ambit (OFC 53.5 cm; −1.3 SD); ambiguous hypertrichosis; nystagmus; brachycephaly, synophrys, symmetrically arranged, vaguely categorical nodules and partly allied plaques accompanied by a down-covered erythema on the forehead, angled eyebrows, balmy blepharophimosis, small/thin nasal root, anteverted nares, anteverted aerial with attenuate helices, abbreviate close (Figure 1d and e), brachydactyly (Supplementary Amount 1); mutual cutaneous syndactyly of fingers II–IV; and mutual cutaneous syndactyly of toes II and III. Neurological assay appear no focal signs. He absolved with baby steps. Subclinical hypothyroidism and hyperlipidemia were additionally present. By belly ultrasound, balmy hepatic steatosis was diagnosed; echocardiography accepted balmy aortic and mitral valve regurgitation.
This accommodating was ahead included in a MR accomplice abstraction (patient 11/3);1 in this abstraction we accommodate a added abundant analytic and atomic characterization.
This changeable accommodating is the alone adolescent of adapted parents, both 26 years old back she was born. Her ancestor was accepted to ache from attack back childhood.
Pregnancy was initially uneventful. Afterwards anniversary 21, IUGR was acclaimed on afresh ultrasound examinations. Commitment took abode at 32 1 weeks by cesarean section. Bearing weight was in the lower accustomed ambit (between 3rd and 10th centile), breadth was at the third centile and microcephaly was acclaimed (head ambit beneath the third centile; −2.4 SD). Shortly afterwards birth, a mandibular neonatal tooth and a bark tag amid on the tragus of the appropriate ear were noticed.
Within the aboriginal weeks of life, weight and breadth alone beneath the third centile. At the age of 1 month, a constant autography Botalli was surgically treated. Motor development was moderately delayed (unsupported sitting at 15 months and aboriginal attempts to clamber at 16 months) and there was no speech.
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Abnormal after-effects of afresh audition tests aloft the suspicion of mutual sensorineural audition loss. She developed able-bodied hypotonia and gastroesophageal reflux, and a assiduous aperture ovale was noted. Cranial MRI scan, EEG and eye assay at the age of 11 months appear no abnormalities. No affirmation for metabolic disorders was found.
At the age of 16 months, the accommodating appeared hardly hypotonic and brachycephaly was observed. Facial dysmorphisms (synophrys, almond-shaped eyes with a mutual epicanthic fold, continued lashes, balmy ptosis, bedfast nasal bridge, anteverted nostrils, continued philtrum and baby aperture with attenuate aerial lip) were noticed. Aerial were baby and posteriorly rotated and the close was short. An aberant Simian bulge was acclaimed on her appropriate hand.
At the age of 84/12 years, the accommodating had developed hyperopia and abstinent MR with apparent hyperactivity. Microcephaly (−3.2 SD) and brachycephaly were observed, and acme and weight were aural the accustomed range. In accession to the facial dysmorphisms declared earlier, her face now appeared annular and hardly flattened, and a baby nasal base and attenuate lower lip were noted. Philtrum and close now had a accustomed length. The two crabbed incisors were missing in her aerial jaw.
The proband is a male, the added adolescent of healthy, non-consanguineous parents. There is no ancestors history of malformations or MR.
He was built-in by ad-lib commitment at 41 weeks of gestational age afterwards an apprehensible pregnancy. APGAR arrangement were 9/10/10. His bearing weight was 2740 g (<3rd centile), breadth 47 cm (<3rd centile) and arch ambit 34 cm (10–25th centile).
At 3 days, the accommodating presented arresting hypotonia, and alternate apneas accompanied by bradycardia afterwards desaturation were observed. He was accordingly accepted to a neonatal accelerated affliction unit, in which a bookish ultrasound showed a appropriate choroid abdomen cyst and subependymal hemorrhage. ECG, echocardiography and fundoscopy were additionally performed with accustomed results.
At 2 and 5 years, academician MRI scans were agitated out absolute no morphological abnormalities. EMG showed accustomed conductance in the anatomy activated and in borderline nerves.
At the age of 5 years and 1 month, he showed a focal epileptic syndrome. He sporadically presented with focal left-sided seizures. Because of the acutely low abundance of the seizures, abiding anti-epileptic assay was never started. EEG recordings showed epileptiform abnormalities over the appropriate axial areas.
The afterward characteristic appearance were observed: brachycephaly, baby aperture with attenuate aerial lip, continued philtrum, anteverted ears, aberrant teeth, mutual epicanthic folds, brachydactyly, pectus excavatum, scoliosis, beef hypotonia and cryptorchidism. Astringent accent and neuromotor adjournment were additionally noted. His behavioral phenotype was characterized by hyperactivity.
At aftermost appraisal (7 years old; Amount 2), the accommodating showed moderate–severe accent and neuromotor retardation. His abstracts were all aural accustomed range. Mutual conductive audition accident was present.
Photographs of case 3 at the age of 7 years, aboveboard (a, c) and crabbed (b) view. Note the alpine forehead, anteverted nares, attenuate aerial lip, anteverted aerial and continued philtrum.
Routine karyotyping by G-banding assay at 400–550 bands was performed application accepted procedures. Array-CGH was performed with the Agilent oligo-platform at a resolution of ~100 Kb (Agilent kit 44B, Agilent, Santa Clara, CA, USA) in all three cases. The procedures for DNA digestion, labeling and admixture were accomplished according to the manufacturer's instructions. Arrangement slides were analyzed by the Agilent scanner (G2505C) with Feature Extraction software (v10.1.1.1). Graphical overviews were acquired application the Agilent DNA analytics software (v4.0.81).
Genotyping of polymorphic loci, quantitative PCR (qPCR), all-embracing PCR (LR-PCR) and DNA sequencing were performed as described.7 The map acclimated for free the genomic positions of probes was Genome Browser Assembly hg18 (http://genome.ucsc.edu). On the base of the aCGH assuming of the deletions, we articular the regions amid aftermost non-deleted and aboriginal deleted probes on anniversary ancillary of the breakpoint. For case 1, we called four about analogously spaced primers on non-repeated portions of the distal breakpoint arena and three primers on the adjacent region, and performed LR-PCRs with all accessible distal/proximal album combinations. One aggregate generated a 4.5-kb fragment that was absolutely sequenced. For case 2, we called three qPCR album pairs in non-repeated portions of the distal breakpoint region, two pairs in the adjacent region, and narrowed both regions bottomward to 3 to 4 kb. We afresh performed LR-PCR and generated a 5-kb fragment that was absolutely sequenced. For case 3, we called four analogously spaced qPCR album pairs in the distal breakpoint arena and eight pairs in the adjacent region. By qPCR, we narrowed both regions bottomward to 6–8 kb, and afresh called three LR-PCR primers on anniversary ancillary and activated all combinations. The beeline consistent fragment (2.5 Kb) was afresh absolutely sequenced.
In the absence of an etiological diagnosis, aCGH was performed to ascertain submicroscopic imbalances in cases 1 and 3 and to redefine the chromosomal breakpoints in the case appear by Engels et al1 (case 2) with the aforementioned arrangement belvedere (Agilent kit 44B; Amount 3b).
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Molecular assuming of the deletions. (a) Map of the 19p13.12–p13.13 region; the deletions are represented by atramentous bars, and the arena of overlap amid the deletions is black in gray. Alone the genes discussed in the argument are shown. According to the Database of Genomic Variants (projects.tcag.ca/variation), several copy-number variations (CNVs), mostly deletions, are begin in the 19p13.12–p13.13 regions. Although some of them (no. 50073, 50074 and 10543) may be acutely attenuate CNVs, others, including no. 5089 and 5090 in the SRO region, accept been detected at actual aerial abundance alone in one address application BAC-array analysis,30 and may accordingly be somewhat unreliable. (b) Aligned aCGH contour capacity of the deletions; the deleted regions are black in gray. (c) Arrangement alignment of the breakpoint junctions; the 3-bp microhomology in case 1 and advisory mismatching bases in cases 2 and 3 are apparent in bold.
The after-effects were:
Case 1: abatement of 1.9 Mb in chromosomal bandage 19p13.12 with breakpoints at 14.119–14.135 Mb and 16.053–16.071 Mb.
Case 2 (Engels et al1: case 11/03): abatement of 2.1 Mb in 19p13.12 with breakpoints at 13.965–13.933 Mb and 16.053–16.118 Mb.
Case 3: abatement of 1.5 Mb in 19p13.12–p13.13 with breakpoints at 12.870–12.878 Mb and 14.154–14.166 Mb.
Typing of advisory polymorphic chromosome 19 markers D19S432 and D19S558 in the deleted breach in cases 1, 3 and their parents showed that in both patients the abatement was of affectionate origin. For case 2, affectionate samples were not accessible to appraise the agent of the deletion.
The breakpoints characterized by aCGH were added authentic by qPCR, amplified by LR-PCR and sequenced in all three cases. The positions and sequences of all junctions are apparent in Amount 3c.
In case 1, a 3-bp ATC microduplication, affirmation of microhomology-related non-homologous end abutting (NHEJ), is present at the junction. The distal breakpoint avalanche in the 3′-end of the LPHN1 gene, admitting the adjacent breakpoint is in intron 2 of TPM4.
In cases 2 and 3, DNA arrangement assay appear that all breakpoints were amid in Alu echo elements and that both deletions originated by Alu-mediated akin recombination. In case 3, the distal breakpoint is in intron 3 of the SYCE2 gene, admitting the adjacent breakpoint is amid amid GIPC1 and DNAJB1. In case 2, the distal breakpoint is in intron 2 of the RFX1 gene, and the adjacent breakpoint in intron 7 of the TPM4 gene. The adjacent breakpoints of cases 1 and 2 are alone 15 kb apart. In cases 1 and 2, the barter does not accomplish any anatomic admixture gene because the genes complex are in adverse orientation. None of the breakpoints is amid aural or abreast segmental duplications.
In this study, we address three patients with partially overlapping microdeletions in 19p13.12. Case 1 was analyzed application aCGH because of his aberrant behavior with adverse conduct characterized by auto- and hetero-aggressivity.
Case 2 was briefly appear by Engels et al1 and belonged to a accomplice of patients called for aCGH because of alien MR. Case 3 was advised for MR and difficult-to-manage hyperactivity.
A allegory of the analytic allegation in the three cases is bedfast by the actuality that the ages of the patients at the times of aftermost appraisal were actual adapted (ie, 7 years, 8412 years and 31 years) and that the oldest patient's history is abridged for the aboriginal months and years of his life. Changes of phenotype with age are able-bodied accurate in patients with chromosomal imbalances.8 To access the numbers of patients and to arch the age gap, we compared the phenotypes of our patients with the afresh appear case2 of a 10-year-old babe accustomed a 2.52-Mb abatement in 19p13.12–p13.13 overlapping the deleted arena in our patients (Figure 3a).
The analytic appearance accepted to our patients and to the case appear by Jensen et al2 are moderate-to-severe psychomotor delay, accent delay, audition accident and facial dysmorphisms including brachycephaly, anteverted nares, as able-bodied as ear malformations. Balmy complete cardiac anomalies and/or accent agitation were empiric at bearing in all cases, and bound spontaneously in the aboriginal years of life, with the barring of balmy aortic and mitral valve amateurishness that was still present at the age of 31 years in case 1 (Table 1).
The four cases allotment a 358 802-bp SRO in which six annotated genes lie: LPHN1/CIRL1, CD97, DDX39, PKN1, PTGER1 and GIPC1 (Figure 3a).
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Two added afresh appear cases backpack 664 Kb5 and 3 Mb4 deletions of 19p13.13–p13.2 partially overlapping the distal allocation (including the SYCE2, NFIX and CACNA1A genes) of the abatement detected in our case 3 (Figure 3a). There is no overlap amid these deletions and those in our cases 1 and 2.
LPHN1/CIRL1 encodes the latrophilin-1 precursor/calcium-independent receptor for α-latrotoxin, a affiliate of the latrophilin subfamily of G-protein accompanying receptors (GPCR) and may action in both corpuscle adherence and arresting transduction. Interestingly, LPHN1 interacts with the PSD-95/discs large/ZO-1 (PDZ) area of the multidomain protein ancestors ProSAP/SSTRIP/Shank.9Shank1 knockout mice appearance abate blooming spines in CA1 cone-shaped neurons and weaker synaptic transmission, forth with adapted acquirements and memory.10 Haploinsufficiency or point mutations of SHANK3, accession affiliate of the SHANK family, after-effects in accent adjournment and/or amusing advice disorders.11, 12 Abatement of LPHN1 may be potentially amenable for the cerebral and accent adjournment and ability accord to the behavioral phenotype empiric in our cases.
The GIPC1 gene, additionally called synectin (MIM 605072), encodes a axle protein that regulates corpuscle apparent receptor announcement and trafficking13 and may be complex in G protein-linked signaling. The GIPC1 gene is annotated in the G2C acknowledgment database (human gene ID: G00001513; abrasion gene ID: G00000264; http://www.genes2cognition.org). Haploinsufficiency of GIPC1 may additionally accord to the brainy and accent adjournment in our patients. In addition, the GIPC1 gene may be a acceptable applicant for the audition crime empiric in all four patients, as its artefact binds to myosin VI,14 encoded by the MYO6 gene. The C442Y missence alteration in this gene may accommodation myosin VI action in a dominant-negative address and account autosomal ascendant nonsyndromic audition loss.15 However, the accommodating declared by Lysy et al4 had mutual audition loss, admitting the actuality that his abatement did not extend to the GIPC1 gene. Furthermore, no audition accident was declared in the Gipc1 knockout mouse.16, 17 Thus, the role of GIPC1 with account to audition crime still charcoal to be clarified.
PKN1 (MIM 601032) codes for a protein acceptance to the protein kinase C superfamily and is active in a array of functions in neurons, including cytoskeleton organization.18 The contempo affirmation that deregulation of PKN1 action disrupts neurofilament alignment and axonal transport19 suggests that its haploinsufficiency may accept an aftereffect on the brainy and accent adjournment in our patients.
The PTGER1 gene (MIM 176802) codes for a protein acceptance to the G protein-coupled receptor family. Ptger1-null mice appearance behavioral inhibition, embodied as abrupt assailment with aberrant amusing interaction, broken bluff abstention and an abstract acoustic affright acknowledgment back beneath amusing or ecology stress.20 Haploinsufficiency of this gene ability be amenable for the astringent behavioral ancestry in case 1 and the hyperactivity in cases 2 and 3.
On the base of the accepted knowledge, abatement of CD97 (MIM 601211) and DDX39 should not accept any aftereffect on patients’ phenotype.
Several contempo affidavit accept apparent that abatement or duplication of the arena crabbed a gene ability additionally be ache causing.21, 22, 23 Thus, we additionally advised genes crabbed the SRO as potentially amenable for the aberrant phenotypes.
On the adjacent ancillary (Figure 3a), SLC1A6 (MIM 600637) codes for a protein that transports L-glutamate, L- and D-aspartate, and seems to act as a symport by cotransporting sodium. It is bidding in the academician and in corpuscle bodies of Purkinje cells. Affiliation studies of polymorphisms in glutamate agent genes showed that SLC1A6 is a susceptibility locus for schizophrenia.24SLC1A6 is deleted in cases 1 and 2, and in the case of Jensen et al.2 Its haploinsufficiency could be amenable for cerebral and accent adjournment in all capacity and may accord to the astringent behavioral phenotype in case 1.
On the distal ancillary (Figure 3a), PRKACA (MIM 601639) codes for a catalytic subunit of the cAMP-dependent protein kinase that is appropriate for abiding potentiation (LTP) in neonatal tissue.25 LTP is anticipation to be alarmingly complex not alone in acquirements and memory, but additionally in neural ambit accumulation and refinement. We advance that haploinsufficiency of PRKACA may be amenable for the cerebral and accent adjournment in cases 2 and 3, and in the accountable appear by Jensen et al,2 and possibly additionally in case 1 if a functionally absent allele for PRKACA was created by a position aftereffect or by disruption of authoritative elements.
Mutations in the CACNA1A gene (MIM 601011) accept been appear in affiliation with attack and cachet epilepticus26, 27, 28 and its haploinsufficiency has been appropriate to be amenable for attack and baby spasms in the case of Auvin et al,5 as able-bodied as for the aberrant electroencephalography in the case of Lysy et al.4CACNA1A abatement is best acceptable amenable for the ad-lib focal seizures in case 3, admitting a positional aftereffect accessory to antipsychotic assay ability accept evoked the epileptic access empiric in case 1.
NFIX (MIM 164005) has an capital role in the development of the academician and skeleton.29Nfix-deficient mice appearance amplification of the crabbed and third academician ventricles and fractional agenesis of the bulk callosum; in addition, they appearance kyphotic anamorphosis of the back and broken endochondral ossification in the base and femur.29 The case of Lysy et al4 showed kyphosis, artogryphosis of lower limb craniosynostosys and abstinent ventriculomegaly;4 Auvin et al5 appear avant-garde cartilage age. As our case 3 does not appearance any of these malformations, the phenotype associated with NFIX haploinsufficiency may action with capricious penetrance.
In conclusion, we declared two new cases of 19p13.12–p13.13 deletions, aesthetic the breakpoints of another1 and compared the abstracts with three appear patients.2, 4, 5 We begin that patients with a 358 802-bp accepted deleted allocation at 19p13.12 are characterized by psychomotor and accent delay, MR, mutual sensorineural and/or conductive audition loss, brachycephaly, anteverted adenoids and ear malformations, as able-bodied as balmy complete cardiac anomalies at birth. Patients with abatement of CACNA1A appearance attack or epileptiform abnormalities on EEG recording. Several genes aural the abatement arena may be associated with MR because of their action and announcement pattern. The best ambrosial amid them are LPHN1, for its alternation with the SHANK proteins, and PKN1. The GPC1 gene may be a applicant for the audition crime empiric in all four patients. Case 1 is the best appropriate accountable because of his difficult-to-manage advancing behavioral phenotype, which was best arresting afterwards adolescence. In cases 2 and 3 hyperactivity was observed. Haploinsufficiency of the PTGER1 gene may be amenable for these behavioral traits.
However, it is additionally accessible that specific phenotypic ancestry are because of a multigene aftereffect associated with several of the abundant genes included in anniversary deletion.
Additional cases, with adapted ages and breakpoints, will advice to ascertain the phenotype and analyze the role of anniversary deleted gene.
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The authors acknowledge no battle of interest.
We acknowledge the families for their cooperation. This assignment was accurate by Italian Ministry of Health admission RF-AOM-2007-636538 to OZ.
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