Table 2.

Summary of clinically relevant CNVs

ID	Chromosome	Event	Pertinent patient phenotypesa
P1b	Xq11.2	55 kb de novo loss including first three exons of ZC4H2	Arthrogryposis, limited mobility of the proximal muscles of the shoulders and lower extremities, spastic paraparesis, abnormal myelination on MRI, bilateral ulnar deviation and shortened deformed fingers, reactive airway disease, dysarthria, and global developmental delay
P2b	22q11.21	434 kb de novo gain	History of multiple bone fractures, hypotonia, delayed motor skills, strabismus, hypermobility, flat feet, and joint pain Note: In addition to the CNV identified, a missense variant in WNT1 was identified providing an explanation for bone fragility and other associated phenotypes
P3bc	Xq13.1	9 kb de novo loss encompassing exon 11 of HDAC8	Delayed motor milestones, hypotonia, intrauterine and postnatal growth retardation, and dysmorphic features suggestive of Cornelia de Lange syndrome
P4b	2p11.2	228 kb maternally inherited gain encompassing REEP1	Demyelinating disease observed on MRI, decreased temperature sensation to cold in the distal lower extremities, decreased sensation to vibration in the distal lower extremities, decreased reflexes, mild dysmetria, and bilateral pes cavus Note: This CNV was inherited from the proband’s mother who was noted to be similarly affected
P5	16p11.2	223 kb tandem duplication on SH2B1	Connective tissue disorder and hypermobile joints, speech delay, speech apraxia, autism, dysmorphic facial features, recent weight loss, short stature, and an abnormal response to traumatic pain Note: Finding likely explains diagnosis of autism and related clinical findings, but there is no evidence to suggest that this patient’s connective tissue disorder is related to this CNV
P6	2q37.2→2qter, 3q29→3qter	Mosaic unbalanced translocation	Dysmorphic facial features and congenital anomalies, with scaphocephaly, prominent metopic ridge, hypoplastic supraorbital ridge, high arched eyebrows, epicanthus inversus, short upslanting palpebral fissures, ptosis, blepharophimosis, narrow upper lip, mild micrognathia or retrognathia, midline cleft palate, patent ductus arteriosus, palmar crease abnormalities, tapered fingers, and hypoplastic nails; notable other phenotypic features include failure to thrive, developmental delay, intellectual disability, profuse sweating during feedings, and tachycardia
P7	2pter→2p25.3, 16q23.3→16qter	Unbalanced translocation	Microcephaly and severe intellectual disability, with no speech and behavioral problems including repetitive, aggressive, and self-abusive behavior; patient described as having sleep difficulties, ataxic walking, and dysmorphic facial features including downslanting palpebral fissures, full lips, frontal upsweep, ptosis, strabismus, and dental crowding
P8	19q13.11-12	1.7 MB de novo deletion	Progressive dystonia, prematurity (born at 28 weeks), dysarthria/anarthria, tongue dyskinesia, microcephaly, abnormal ocular movements, intellectual disability, some repetitive obsessive behaviors, and pyramidal tract signs on MRI; nonverbal and does not walk or eat independently; described as thin-appearing
P9	18p	Tetrasomy 18p	Severe global developmental delay, nonverbal, ataxia, feeding difficulties, strabismus, aggressive behavior, dysmorphic features including occipital plagiocephaly, downslanting short palpebral fissures, low-set posteriorly rotated malformed small ears, smooth philtrum, mild prognathism, bilateral camptodactyly in the 3rd, 4th, and 5th fingers with absent distal interphalangeal creases, hypoplastic thenar eminences, and a right single transverse palmar crease; facial paralysis as an infant and asymmetric crying face
P10	8p23.1	5.1 Mb gain (unknown de novo or inherited)	Intermittent rash; telangiectasia; acroparesthesia; numbness, pain, and swelling of extremities; joint pain; facial flushing; and headaches; CT scan revealed hypoperfusion in the left parietal lobe relating to ischemia; he also has hypertrophic cardiomyopathy, bradycardia, expressive speech delay, and a learning disability
P11	6q22.1-31, 6q23.1, 11p15.4-3	Multiple large deletions on 6q, inserted duplication of 11p into chr17	Growth deficiency, microcephaly, intellectual disability with no speech, hyperactivity, large bulbous nose, epicanthal folds, short philtrum, small mandible, seizures; family history is pertinent for two maternal uncles who have little or no speech
P12	14q32.2	23 kb de novo mosaic deletion to the promoter of MEG3	Developmental delay, speech delay, behavioral difficulties, neonatal respiratory and feeding difficulties, hyperextensible and buckling phalanges, bilateral hallux valgus, and dysmorphic features including full cheeks, myopathic facies, prognathism, thick pinnas, strabismus, short forehead, bifrontal narrowing, midface hypoplasia, and anteverted nares
P13	15q11.2	604 kb maternally inherited deletion of BP1–BP2 in the Burnside–Butler susceptibility locus	Episodes of ataxia, cyanosis, memory disturbance, speech difficulty, emesis, and severe pain in arms and legs, easy fatigue, constipation alternating with diarrhea, possibly due to intestinal dysmotility, as well as general abdominal distension and possible intussusception; ventricular tachycardia, frequent respiratory infections and rashes, and possible small fiber neuropathy were also noted; differential diagnoses include dysautonomias, mitochondrial disorders, energy depletion syndromes, and mast cell abnormalities
P14	16p13.11	1.6 Mb gain, unknown inheritance	Congenital inflammatory myopathy, hypotonia, muscle pain, absent reflexes, and motor delay; a muscle biopsy showed necrosis and paleness of sarcoplasma with eosinophilia, multiple vacuoles, and inflammatory infiltrate Note: This CNV was reported as a pathogenic incidental finding for 16p13.11 microduplication syndrome
P15	7p22.1	749 kb deletion in PSM2	Phenotype not applicable as CNV was discovered upon Secondary Findings analysis
P16	chr21	Trisomy 21	Clinical diagnosis of Down syndrome (confirmed by karyotype). Additionally, patient is reported to have phenotypic features that are not consistent with a diagnosis of trisomy 21, including hypotonia that is more marked than expected, dermal ridge patterns with more arches than are typical, a small phallus, infantile spasms that are controlled on medication, a skeletal and long myopathic face, lumbar lordosis, scapular winging, tapered calves, absent reflexes, ptosis, and a lurching pelvis when walking. The patient is unable to walk without a walker. Family history is notable for nemaline myopathy. The patient’s mother’s phenotype includes weakness in childhood and a muscle biopsy revealing nemaline rods, consistent with a diagnosis of nemaline myopathy. She could not run or jump as a child, although her clinical presentation improved over time. Currently, she is reported to have few residual features although she cannot run. Note: CNV analysis revealed trisomy 21; in addition, a maternally inherited variant classified as likely pathogenic in ACTA1 was identified in both the proband and mother
P17c	chr14	Mosaic trisomy 14	Developmental delay, ocular colobomas, low-set posteriorly rotated ears, hypomelanosis of Ito, solitary kidney, atrial and ventricular septal defects
P18c	chr15	UPD15, paternal	Global developmental delay with language delay, strabismus, coxa vulga, genu valgum, pes planus, low-set cupped ears with attached lobe, broad palate with alveolar ridge, short neck, inverted nipples, truncal obesity, broad-based ataxic gait, hypotonia, and lumbar lordosis
P19b,c	chr16	UPD 16, paternal	Hypotonia, developmental delay, diffuse pachygyria with leukoencephalomalacia Note: Paternally inherited UPD 16 was considered an incidental finding for this patient as there is no evidence linking paternal UPD 16 in association with disease

Note that these variants are not used in the aggregate statistics reported here.

CNV copy-number variant, MRI magnetic resonance image, UPD uniparental disomy.

^aPatient phenotypic data were provided to Illumina Clinical Services Laboratory by the ordering physician via the completed test requisition form and accompanying medical notes.

^bSample sequenced in prevalidation test development cohort. Note that these samples are not used in any reported aggregate statistics.

^cVariant is outside of the clinical test definition but was observed in a development pipeline or as an incidental finding.