TY - JOUR
AU - Dong,, Jianli
AB - Abstract Chromosome 16p11.2 is one of the susceptible sites for recurrent copy number variations (CNVs) due to flanking near-identical segmental duplications. Five segmental duplications, named breakpoints 1 to 5 (BP1–BP5), have been defined as recombination hotspots within 16p11.2. Common CNVs on 16p11.2 include a proximal ~593 kb between BP4 and BP5, and a distal ~220 kb between BP2 and BP3. We performed a search for patients carrying 16p11.2 CNVs, as detected using chromosome microarray (CMA), in the Molecular Diagnostic Laboratory at the University of Texas Medical Branch (UTMB), in Galveston. From March 2013 through April 2018, a total of 1200 CMA results were generated for germline testing, and 14 patients tested positive for 16p11.2 CNVs, of whom 7 had proximal deletion, 2 had distal deletion, 4 had proximal duplication, and 1 had distal duplication. Herein, we provide detailed phenotype data for these patients. Our study results show that developmental delay, abnormal body weight, behavioral problems, and hypotonia are common phenotypes associated with 16p11.2 CNVs. chromosome 16p11.2, copy number variation, chromosome microarray, genotype-phenotype correlation, developmental delay, phenotypic heterogeneity Segmental duplications, also known as low-copy repeats (LCRs), can mediate misalignment of DNA sequences leading to deletions and duplications.1,2 The 16p11.2 region has been identified as a prevalent hotspot for deletions and duplications.3–7 Within this hotspot, 5 segmental duplications have been identified and named breakpoint (BP)1 to BP5, from telomere to centromere.8,9 Common DNA copy number variations (CNVs) on 16p11.2 include a proximal ~593 kb region located between BP4 and BP5 at the approximate position of 29.6 to 30.2 Mb, and a distal ~220 kb region located between BP2 and BP3 at the approximate position of 28.8 to 29.0 Mb, both in the reference genome GRCh37/hg19.8–10 Overall, 16p11.2 CNVs have been categorized into 3 main syndromes: deletion of the proximal region (OMIM 611913), reciprocal duplication of the proximal region (OMIM 614671), and deletion of the distal region (OMIM 613444). In addition to neurocognitive phenotypes, such as autism, epilepsy, and developmental delay with coexisted congenital anomalies, these proximal CNVs have been identified in patients who present with increased risk for neuroblastoma, cardiac defects, renal cysts, obesity, scoliosis, and vertebral anomalies.7,8,11–16 The proximal deletion was associated with macrocephaly, autism, obesity, and hyperphagia, whereas the reciprocal duplication was associated with microcephaly, schizophrenia, and underweight (mirror traits).15,17,18 Besides these main phenotypes, other phenotypes are exhibited with a lower degree of penetrance.19 The distal deletion was associated with obesity, which is strongly associated with deletion of the SH2B1 gene, as well as autism, macrocephaly, and scoliosis.20–23 Our purpose in this research work was to examine phenotypes associated with 16p11.2 CNVs. We identified 14 patients at our institution, 9 of whom had 16p11.2 deletions and 5 of whom had 16p11.2 duplications, during an approximately 5-year period ending in April 2018. We analyzed the clinical features of these 14 patients and herein report our findings on their detailed phenotypes. Materials and Methods Editorial Policies and Ethical Considerations This study was approved by the University of Texas Medical Branch (UTMB) institutional review board. Patients were not directly informed, and informed consent was not required. Selection of Patients All 16p11.2 CNVs were identified through testing by chromosome microarray (CMA) in the Molecular Diagnostic Laboratory at UTMB. The Molecular Diagnostics Laboratory has performed CMA testing from March 2013 through April 2018, generating approximately 1200 CMA results for germline testing. Chromosome Microarray Methods CMA testing was performed on peripheral blood specimens. The specimens were analyzed using CytoScan HD (Thermo Fisher Scientific Inc) according to manufacturer-provided instructions, as previously described.24 CNVs were examined and interpreted according to practice guidelines.25,26 Medical Records Review Medical records for the 14 patients identified by CMA testing were reviewed for medical and developmental history, presenting signs and symptoms, and other relevant information. Growth charts for height, weight, body mass index (BMI; weight in kg divided by height in m2), and weight-for-length were used to track growth progress and development of body weight over time. In categorizing body weight, weight-for-length was used for the period from birth to <2 years, and BMI was used for ages 2 through 20 years. Patients were categorized as obese when either of these measurements were at or above the 95th percentile. Conversely, patients were categorized as underweight when either of these measurements was at or less than the 5th percentile. Macrocephaly and microcephaly were indicated when head circumference was equal to the 95th percentile or greater, or the 5th percentile or less, respectively, of the range for the same age and sex. Results CNVs in 16p11.2 were detected in 1.17% of cases (14/1200) submitted for CMA testing at the UTMB Molecular Diagnostics Laboratory. The 14 cases included 7 patients with a proximal deletion, 2 with a distal deletion, 4 with a proximal duplication, and 1 with a distal duplication (Figure 1). Ten of our 14 patients were referred for CMA testing for evaluation of developmental delay; 3 for intellectual disability; and 1 for procreative management due to diagnosis, in the daughter of one of the other case patients, of 16p11.2 deletion syndrome, 220 kb (Table 1). Among the patients with 16p11.2 deletions, all 9 patients were white; among the patients with 16p11.2 duplications, 3 were white and 2 were African American. Ages given are at the time of CMA testing. Figure 1 Open in new tabDownload slide Gains and losses of 16p11.2 regions in the 14 cases. Copy number variations (CNVs) in 16p11.2 in 14 case individuals at the University of Texas Medical Branch (UTMB) Molecular Diagnostics Laboratory. BP indicates breakpoint. Figure 1 Open in new tabDownload slide Gains and losses of 16p11.2 regions in the 14 cases. Copy number variations (CNVs) in 16p11.2 in 14 case individuals at the University of Texas Medical Branch (UTMB) Molecular Diagnostics Laboratory. BP indicates breakpoint. Table 1. Phenotypes for Case Individuals with 16p11.2 CNVs Patient # . Sex . Age, y . Reason for Referral . DD . S/LD . MD . DFF . Head Size Abnormality . Body Weight Category . Behavioral Problema . ASD . Seizure . Muscle Tone Problem . Other . 1 F 3 MD yes yes yes yes no normal no no no Hypotonia no 2 M 36 Reference for patient 1 NA NA NA NA no normal no NA no no no 3 M 9 DD yes yes yes yes Macrocephaly obese Yes NA no Hypotonia yes 4 M 5 DD yes yes yes yes no normal no NA no Hypotonia no 5 M 9 DD yes yes no yes no obese yes NA no Hypotonia yes 6 M 9 DD yes yes no yes no obese yes NA no Hypotonia yes 7 M 12 ID yes yes yes yes no normal yes no no no no 8 M 11 ID no yes no no no obese no no no no yes 9 M 5 DD yes yes yes yes no normal yes yes yes no no 10 F 7 DD yes yes no no no normal yes no no no no 11 F 16 ID yes yes yes no no normal no no no yes yes 12 F 9 DD yes yes yes no no normal no yes no no no 13 M 8 DD yes yes yes no Macrocephaly normal yes no no no no 14 F 5 DD yes yes yes yes microcephaly underweight no no no hypotonia yes Patient # . Sex . Age, y . Reason for Referral . DD . S/LD . MD . DFF . Head Size Abnormality . Body Weight Category . Behavioral Problema . ASD . Seizure . Muscle Tone Problem . Other . 1 F 3 MD yes yes yes yes no normal no no no Hypotonia no 2 M 36 Reference for patient 1 NA NA NA NA no normal no NA no no no 3 M 9 DD yes yes yes yes Macrocephaly obese Yes NA no Hypotonia yes 4 M 5 DD yes yes yes yes no normal no NA no Hypotonia no 5 M 9 DD yes yes no yes no obese yes NA no Hypotonia yes 6 M 9 DD yes yes no yes no obese yes NA no Hypotonia yes 7 M 12 ID yes yes yes yes no normal yes no no no no 8 M 11 ID no yes no no no obese no no no no yes 9 M 5 DD yes yes yes yes no normal yes yes yes no no 10 F 7 DD yes yes no no no normal yes no no no no 11 F 16 ID yes yes yes no no normal no no no yes yes 12 F 9 DD yes yes yes no no normal no yes no no no 13 M 8 DD yes yes yes no Macrocephaly normal yes no no no no 14 F 5 DD yes yes yes yes microcephaly underweight no no no hypotonia yes CNVs, copy number variations; DD, developmental delay; S/LD, speech/language delay; MD, motor delay; DFF, dysmorphic facial features; ASD, autism spectrum disorder; NA, not available; ID, intellectual disability. aIncludes attention-deficit/hyperactivity disorder (ADHD), schizophrenia, etc. Open in new tab Table 1. Phenotypes for Case Individuals with 16p11.2 CNVs Patient # . Sex . Age, y . Reason for Referral . DD . S/LD . MD . DFF . Head Size Abnormality . Body Weight Category . Behavioral Problema . ASD . Seizure . Muscle Tone Problem . Other . 1 F 3 MD yes yes yes yes no normal no no no Hypotonia no 2 M 36 Reference for patient 1 NA NA NA NA no normal no NA no no no 3 M 9 DD yes yes yes yes Macrocephaly obese Yes NA no Hypotonia yes 4 M 5 DD yes yes yes yes no normal no NA no Hypotonia no 5 M 9 DD yes yes no yes no obese yes NA no Hypotonia yes 6 M 9 DD yes yes no yes no obese yes NA no Hypotonia yes 7 M 12 ID yes yes yes yes no normal yes no no no no 8 M 11 ID no yes no no no obese no no no no yes 9 M 5 DD yes yes yes yes no normal yes yes yes no no 10 F 7 DD yes yes no no no normal yes no no no no 11 F 16 ID yes yes yes no no normal no no no yes yes 12 F 9 DD yes yes yes no no normal no yes no no no 13 M 8 DD yes yes yes no Macrocephaly normal yes no no no no 14 F 5 DD yes yes yes yes microcephaly underweight no no no hypotonia yes Patient # . Sex . Age, y . Reason for Referral . DD . S/LD . MD . DFF . Head Size Abnormality . Body Weight Category . Behavioral Problema . ASD . Seizure . Muscle Tone Problem . Other . 1 F 3 MD yes yes yes yes no normal no no no Hypotonia no 2 M 36 Reference for patient 1 NA NA NA NA no normal no NA no no no 3 M 9 DD yes yes yes yes Macrocephaly obese Yes NA no Hypotonia yes 4 M 5 DD yes yes yes yes no normal no NA no Hypotonia no 5 M 9 DD yes yes no yes no obese yes NA no Hypotonia yes 6 M 9 DD yes yes no yes no obese yes NA no Hypotonia yes 7 M 12 ID yes yes yes yes no normal yes no no no no 8 M 11 ID no yes no no no obese no no no no yes 9 M 5 DD yes yes yes yes no normal yes yes yes no no 10 F 7 DD yes yes no no no normal yes no no no no 11 F 16 ID yes yes yes no no normal no no no yes yes 12 F 9 DD yes yes yes no no normal no yes no no no 13 M 8 DD yes yes yes no Macrocephaly normal yes no no no no 14 F 5 DD yes yes yes yes microcephaly underweight no no no hypotonia yes CNVs, copy number variations; DD, developmental delay; S/LD, speech/language delay; MD, motor delay; DFF, dysmorphic facial features; ASD, autism spectrum disorder; NA, not available; ID, intellectual disability. aIncludes attention-deficit/hyperactivity disorder (ADHD), schizophrenia, etc. Open in new tab Distal Deletions Patients 1 and 2 were a daughter-father duo. Patient 1 was a 3-year-old white girl with a distal deletion. She had overall developmental delay and continued to walk with hip rotation rather than hip and knee flexion; she tested negative for autism. This patient had dysmorphic facial features, hypotonia, and a very low tone of hypermobile joint movement, along with continued feeding difficulties. Laryngomalacia, ankyloglossia, deviated septum, and oropharyngeal dysplasia had been diagnosed during her infancy. Her body weight and head circumference were normal (Table 1, Supplemental Tables 2–3). Patient 2, the father of patient 1, is a 35-year-old white man. In addition to having the same distal deletion as his daughter, this man was found to have a 1386 kb gain on chromosome 22q11.23; ARR[GRCh37] 22q11.23(23,652,517_25,038,276) × 3. Overall, this patient was phenotypically normal. No information was available regarding his childhood development or any behavioral problems. Some of us had previously reported the case of this patient;24 (Case 6). Proximal Deletions Patient 3 was a 9-year-old white boy with global developmental delay. He had been diagnosed with attention-deficit/hyperactivity disorder (ADHD) but never tested for autism. He had been diagnosed with macrosomia when he was a newborn. He had very thick hair and a low hairline, coarse facial features, large pinna, synophrys, and esotropia. His mouth appeared small, with missing front upper incisors and conical canines. Also, he had hypotonia, testicular atrophy, asthma, and allergic rhinitis (Table 1). His birth weight was in the normal range, at the 36th percentile. At age 30 months and at 4 years and 9 months, he was classified as having obesity, with a BMI greater than the 99.99th percentile. At 4 years 7 months, his head circumference was at the 94th percentile; 2 months later, that measurement was greater than the 95th percentile (Supplemental Tables 2–3). Patient 4 was a 5-year-old white boy who demonstrated developmental delay. He had a significant mixed receptive-expressive language disorder, without a consistent functional method of communication. His expressive language skills appeared to be more affected than his receptive language skills. He was not tested for autism-spectrum disorder (ASD). He did not have dysmorphic facial features but he had large pinna and slightly low-set ears. He was also noted to have low neuromuscular tone. His body weight and head size were normal (Table 1, Supplemental Tables 2–3). Patients 5 and 6 were 9-year-old identical twin white brothers with the same proximal deletion. Both boys had global developmental delay, speech delay, and ADHD, as well as pyloric stenosis at age 2 weeks, unevaluated heart murmur, asthma, seasonal allergies, migraines, obstructive sleep apnea, photophobia, phonophobia, and farsightedness. Patient 6 was described as having more-delayed mental status. Both twins had dysmorphic facial features. However, although both had upslanting palpebral fissures, Patient 5 had more dysmorphic facial features, including craniofacial dysmorphology comprising bilateral ptosis, flat nasal bridge, possible hypertelorism, micrognathia, and low-set ears, as well as pes planus (Table 1). Both twins had BMI measurements in the obese category, but their head circumferences were in the normal range. It was reported that patient 5 had been underweight until age 5 years and then had rapidly gained weight in the following years (Supplemental Tables 2–3). Patient 7 was a 12-year-old white boy who presented with developmental delay and mixed receptive-expressive language disorder. He also presented with social anxiety, bipolar disorder, dyslexia, and low visual perceptional skills but not ASD. He had mild dysmorphic features, including low-set ears, left Darwinian tubercle, nonsmooth philtrum, missing teeth, and a malaligned front tooth. Also, he had muscle weakness, a high-arched but functional hard palate, seasonal hyponasality, seasonal allergic rhinitis, hyperopia, migraines, and a history of 1 seizure caused by head trauma (Table 1). His body weight and head size were normal (Supplemental Tables 2–3). Patient 8 was a 11-year-old white boy with a unique proximal deletion. Overall, he did not present with developmental delay but he had a mild speech development disorder, severely impaired receptive and expressive language skills, learning disabilities, and anxiety, and he was prone to hasty or stress eating. Autism was not suspected. He did not have any dysmorphic features but he presented with asthma without complication and allergic rhinitis, and he had been evaluated for an undescended testis at age 7 years. At age 5 years 1 month, his BMI had been at the 96th percentile. At 11 years 7 months, he had obesity, with a BMI greater than the 99.99th percentile (Table 1, Supplemental Tables 2–3). The CNV region for patient 9 is more like that in patient 3 than in other patients with proximal deletions, with an additional 0.1 Mb for the minimum position (Figure 1, Supplemental Table 1). Patient 9, a 5-year-old white boy, presented with developmental delay and severely impaired expressive and receptive language skills. He had low-grade ASD and ADHD. This patient had persistent feeding difficulties and a history of 1 seizure caused by respiratory syncytial virus infection. He had dysmorphic features, including curved eyebrows, a broad forehead, and deep-set eyes with prominent brows, a history of eustachian-tube dysfunction in both ears, joint swelling, arthralgias, and gait problems resulting from knee swelling at the age of 3 years. His body weight and head size were normal (Table 1, Supplemental Tables 2–3). Proximal Duplications Patient 10 was a 7-year-old white girl who demonstrated overall developmental delay. Her presentation included speech delay and sporadic hyperactivity, but autism was not suspected. She did not have dysmorphic features but she had abnormal auditory perception and myopia. Her body weight and head size were normal (Table 1, Supplemental Tables 2–3). Patient 11 was a 16-year-old black girl who demonstrated global developmental delay. She presented with motor delay with a spastic gait, trouble walking, and impaired mobility and activities of daily life. She did not have dysmorphic features but she was affected by vesicoureteral reflux, abnormal auditory perception, and myopia. Her diagnoses included Dubowitz syndrome (characterized by cognitive disability, short stature, microcephaly, abnormal facial features, hyperactivity, aggressiveness, and a short attention span)27 and cerebral palsy, and she required the use of a wheelchair. She had difficulty walking, contracted joints at multiple sites, abnormally low muscle tone due to muscle atrophy, and spasticity. Her gait was abnormal, comprising toe walking and turned-out feet, and had undergone percutaneous tendon release at approximately age 6 years. Also, she had a history of bony occipital deficit. Her body weight and head size were normal (Table 1, Supplemental Tables 2–3). The patient also tested positive for a duplication of 646 kb on 5q23.3; ARR[GRCh37] 5q23.3(129,349,930_129,996,026) × 3. Gains within this region have been interpreted as likely benign/variant of uncertain significance (VUS) in ClinVar and DECIPHER (RCV000135225, https://www.ncbi.nlm.nih.gov/clinvar/; patients 289,714 and 394,728, https://decipher.sanger.ac.uk/). The contribution of this gain to the phenotypes of our patients is uncertain. Patient 12 was a 9-year-old white girl who presented with gross motor delay, fine motor delay, and marked speech delay. Also, she was reported to display a high degree of hyperactivity at times. She was not diagnosed with ASD. She had no dysmorphic facial features but was affected by myopia. Her body weight and head size were normal (Table 1, Supplemental Tables 2–3). Patient 13 was an 8-year-old black boy who presented with mixed receptive-expressive language disorder and overall developmental delays. He was not diagnosed with ASD but he presented with ADHD and hyperactivity. Although he did not have major dysmorphism of facial features, he had mild exophoria. He also had impaired vision, myopia, and astigmatism. He had normal body weight, but his head size was larger (Table 1, Supplemental Tables 2–3). This patient also tested positive for an 862 kb deletion on chromosome 2q13; ARR[GRCh37] 2q13(110,504,318_111,365,996) × 1, a pathogenic variant with symptoms including developmental delay, abnormality of the cerebrum, and chronic kidney disease/renal insufficiency (ClinGen cases nssv582701, nssv582770, nssv582862, nssv579952, and nssv1610267; https://www.ncbi.nlm.nih.gov/clinvar/). Distal Duplication Patient 14 was a 5-year-old white girl who had a distal duplication. She had overall developmental delay and was not diagnosed with ASD. She had mild dysmorphia, with low-set ears and triangular facies. She was noted at birth to have moderate plagiocephaly of the right occipital region of the head, hyperbilirubinemia of prematurity, respiratory distress syndrome, and a reducible umbilical hernia. Cardiologic evaluation of a heart murmur revealed a small secundum atrial septal defect and a tiny patent ductus arteriosus, but the cardiac anatomy and function were otherwise normal. The patient also had low muscle tone and hypermobile joint movement. At birth, she was borderline underweight (weight-for-length at the ~5th percentile) and had microcephaly (head circumference  < the 1st percentile). At age 4 years 4 months, her head circumference had remained at less than the 5th percentile. At 5 years 4 months, her BMI was in the underweight category, at less than the 0.01th percentile (Table 1, Supplemental Tables 2–3). Discussion This study focused on a small cohort of patients who underwent CMA testing at UTMB and were found to have CNVs on chromosome 16p11.2. Of the 14 patients described herein, 7 had proximal deletion, 2 had distal deletion, 4 had proximal duplication, and 1 had distal duplication (Figure 1). Eight of the nine deletion carriers were male, whereas four of the five duplications were female (almost all patients with deletions are male, almost all patients with duplications are female; Table 1, Figure 1). The clinical significance of the sex differences is unknown and should be further explored in future studies. Patients 1 and 2 of the UTMB cohort, the daughter-father pair, represent a good demonstration of the incomplete penetrance of the 16p11.2 CNVs. Although the breakpoint regions for the 2 patients were similar, the daughter presented with many of the abnormal phenotypes commonly associated with the CNV, whereas the father did not present with an abnormal phenotype. Patients 5 and 6, the twin brothers, demonstrate the somewhat variable expressivity observed with the 16p11.2 CNVs. Overall, the brothers share the same phenotypes, such as developmental delay, dysmorphic facial features, obesity, and behavioral problems. However, the specific phenotypic details vary slightly, such as the progression of body weight and specific dysmorphic facial features. Sharing the same genetics, breakpoints, and overall phenotypes, these twins showcase the phenotypic variability of the CNVs. Looking at the major phenotypes found to be associated with 16p11.2 CNVs, only 1 in 6 patients with proximal deletion presented with macrocephaly and 1 (of 3 tested) with ASD. Similarly, none of the patients with proximal duplication had microcephaly. Although these are more commonly reported phenotypes, these phenotypes present with phenotypic heterogeneity and mirror phenotypes.17,18,28 Further, 4 of 7 patients with proximal deletion and 1 of 4 patients with reciprocal duplication presented with obesity, which further illustrates heterogenic phenotypes.15 Patient 14 was the only patient who presented with distal duplication, which is not reported in the OMIM database. We found only 4 articles in the literature22,29–31 that reported cases of distal duplication with associated presentations including decreased intracranial volume and scoliosis. The reported cases presented phenotypes that mirrored those associated with distal deletion (eg, decreased weight and BMI, decreased body fat, and microcephaly, as well as scoliosis). Three cases with 16p11.2 distal duplications are noted in DECIPHER and interpreted as VUS/likely pathogenic (patients 282,293, 288,488, and 303,556; https://decipher.sanger.ac.uk/). The associated phenotypes are intellectual disability, cognitive impairment, delayed speech and language development, and dolichocephaly. The UTMB patient presented with developmental delay, speech and language delay, motor delay, dysmorphic facial features, microcephaly, and hypotonia (Table 1). Case 14 can add to the existing pool of cases of distal duplications. However, additional cases should be analyzed to better evaluate common phenotypes associated with this CNV and their rate of occurrence. The genomic structure and gene content of the 16p11.2 CNVs were interrogated using the UCSC (University of California Santa Cruz) Browser; Supplemental Table 1 identifies genes found in the CNV region for the 14 patients we studied. Many of the genes have been shown to be associated with neurodegenerative disorders, which would involve development of the brain and overall head size and would explain the link with the wide range of behavioral problems, including ASD and hyperactivity (OMIM 611,913, 614671, and 613444). After comparing genes shared among the patients with deletions/duplications of the proximal region using UCSC Browser, the minimal region is found to be located between genes SMG1P2 and MAPK3 (Supplemental Table 1). Although the minimum position both deletion and duplication cases were very similar, the maximum position for the deletion cases differed greatly from that of the duplication cases. The duplication cases shared the same maximum position, which includes CORO1A, BOLA2B, SLX1A, and SULT1A4 genes; however, the minimal region for the deletion cases did not include these genes. Reference 32 identified a ~118 kb deletion within the proximal region that includes 5 genes (MVP, CD1PT1, SEZ6L2, ASPHD1, and KCTD13) as primary candidate for ASD.32 In reference 29, the researchers found that KCTD13 is a major driver of mirrored neuroanatomical phenotype of 16p11.2 CNVs, in which its overexpression and suppression were associated with microcephaly and macrocephaly, respectively. Analyses of DECIPHER entries (https://decipher.sanger.ac.uk/) within regions of the 16p11.2 CNVs, as well as 22q11.23 gain (case 2), 5q23.3 gain (case 11), and 2q13 loss (case 13), show that these CNVs can be maternally or paternally inherited. Whether there is parent-of-origin bias and if so, whether such bias influences phenotypic expression of these CNVs need to be explored. The current study uses available cases to compare genotypic breakpoints and to identify phenotypes expressed with the 16p11.2 CNV regions and the involved genes that may influence the expressed phenotypes. Further research is necessary to further understand phenotypic expression of 16p11.2 CNVs (Supplemental Tables 1 and 2). LM Abbreviations Abbreviations LCRs low-copy repeats BP breakpoint CNVs copy number variations UTMB University of Texas Medical Branch CMA chromosome microarray BMI body mass index ADHD attention-deficit/hyperactivity disorder ASD autism-spectrum disorder VUS variant of uncertain significance UCSC University of California Santa Cruz DD developmental delay S/LD speech/language delay MD motor delay DFF dysmorphic facial features NA not available ID intellectual disability Acknowledgments We thank Kathryn Hale, MS at Scientific Publications, Research Medical Library of MD Anderson Cancer Center, Houston, TX, for her editing of the initially submitted manuscript. Supplementary Data Supplemental Tables can be found in the online version of this article at www.labmedicine.com. References 1. Gu W , Zhang F, Lupski JR. Mechanisms for human genomic rearrangements . 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TI - Phenotypes Associated with 16p11.2 Copy Number Gains and Losses at a Single Institution
JF - Laboratory Medicine
DO - 10.1093/labmed/lmaa026
DA - 2002-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/phenotypes-associated-with-16p11-2-copy-number-gains-and-losses-at-a-1mIQElyvN8
SP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -