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Table 4 Clinically relevant findings in a prospective study of 100 cases referred for CMA

From: From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability

Case Reason for referral CNVs (ISCN 2016) Size Classification OMIM diagnosis (inheritance pattern) Added information by WGS
Fifteen CNVs detected with CMA and WGS
 RD_P403 NDD arr[GRCh37] 2p21p22.1(39053852_42501893)x3 dn 3.45 Mb Likely pathogenic Not in OMIM Tandem duplication
 RD_P404 NDD arr[GRCh37] 3p25.2p25.3(9453917_12015126)x3 2.56 Mb Likely Pathogenic Not in OMIM Tandem duplication
 RD_P405 Growth retardation arr[GRCh37] 3q25.32q26.1(158567751_160802139)x3 (not paternal) 2.23 Mb Likely Pathogenic Not in OMIM Duplication inserted on chromosome 13
 RD_P406 NDD, microcephaly arr[GRCh37] 4q25q35.2(190816609_191024533)x3 dn 81 Mb Pathogenic Not in OMIM Unbalanced translocation between chr 4 and chr2
 RD_P407 NDD, Arthrogryposis arr[GRCh37]
7q11.23(72699382_74142329)x1 dn
1.44 Mb Pathogenic #194050
Williams-Beuren syndrome (AD)
 RD_P408 Short stature, NDD, facial dysmorphism arr[GRCh37]
7q11.23(72726590_74142329)x1 dn
1.42 Mb Pathogenic #194050
Williams-Beuren syndrome (AD)
 RD_P409 Hypogonadotropic hypogonadism arr[GRCh37]
8p11.22(38320755_38328265)x1 dn (exon 1 FGFR1)
7.52 kb Pathogenic #147950 Kallmann syndrome (AD)  
 RD_P410 Duodenal atresia arr[GRCh37] 9p24.2p24.3(2074076_2381053)x1 pat 307 kb VUS Not in OMIM  
 RD_P411 NDD, Arthrogryposis arr[GRCh37] 12q13.13(53784698_54741363)x1 dn 957 kb Pathogenic Not in OMIM  
 RD_P412 NDD arr[GRCh37] 15q13.2q13.3(30405535_32914190)x1 2.5 Mb Pathogenic #612001
15q13.3 microdeletion syndrome (AD)
 RD_P413 NDD arr[GRCh37]
502 kb Pathogenic #611913
16p11.2 microdeletion syndrome (AD)
 RD_P414 NDD arr[GRCh37]
18p11.32pter(12774-1652788)x1 dn,
18q22.1qter(62984563_78015117)x1 dn
(Ring chromosome)
1.64 Mb
15 Mb
Pathogenic Not in OMIM Detailed structure of derivative chromosome
 RD_P415 NDD arr[GRCh37] 22q11.21(18890264_21540347)x1 2.65 Mb Pathogenic #188400
DiGeorge syndrome (AD)
 RD_P416 NDD arr[GRCh37] 2q23.1(148893848_148944832)x1
(exon 3 MBD5)
51 kb VUS #156200
Intellectual disability 1 (AD)
One CNV detected with WGS
 RD_P417 NDD arr[GRCh37] 12q24.31(123736705_123740392)x0 (exon 2 C12orf65) 3.7 kb Pathogenic #613559
Combined oxidative phosphorylation deficiency 7 (AR)
Deletion found by WGS and not detected by CMA
Case Reason for referral SNV Inheritance Zygosity OMIM diagnosis Classification
Nine SNVs detected with ID in silico gene panel
 RD_P418 NDD, macrocephaly NSD1, NM_172349, c.5289G>C, p.(Trp1763Cys) De novo Heterozygous #117550
Sotos syndrome (AD)
Likely Pathogenic
 RD_P419 NDD (father with similar symptoms) NKX2-1, NM_003317, c.556delC, p.(Leu186CysfsTer12) Paternal Heterozygous #610978
Choreoathetosis, hypothyroidism and neonatal respiratory distress (AD)
Likely Pathogenic
 RD_P420 NDD, white matter abnormality PNPT1, NM_033109, c.420delG; p.(Leu141SerfsTer17)
PNPT1, NM_033109, c.1519G>T, p.(Ala507Ser)
Paternal Compound heterozygous #614932
Combined oxidative phosphorylation deficiency 13 (AR)
Likely Pathogenic
 RD_P421 NDD, cleft-lip palate SATB2, NM_015265, c.652A>T, p.(Lys218Ter) De novo Heterozygous #612313
Glass syndrome (AD)
 RD_P422 Microcephaly, holoprocencephaly ZIC1, NM_007129, c.1225C>T, p.(Arg409Trp) De novo Heterozygous #616602
Craniosynostosis 6 (AD)
Likely Pathogenic
 RD_P423 NDD, macrocephaly PTEN; NM_000314, c.264T>G; p.(Tyr88Ter) N.i. Heterozygous #158360
Cowden syndrome (AD)
Likely Pathogenic
 RD_P424 Respiratory failure, abnormality of corpus callosum POLG; NM_002693, c.679C>T;679C>T, p.(Arg227Trp) Paternal/
Homozygous #203700
Mitochondrial DNA depletion syndrome 4A (AR)
Likely Pathogenic
 RD_P425 NDD, epilepsy CLN5, NM_006493, c.595C>T;595C>T, p.(Arg199Ter) Paternal/
Homozygous #256731
Ceroid lipofuscinosis, neuronal 5 (AR)
 RD_P426 NDD, dysmorphic features , macrocephaly ANKRD11; NM_013275, c.3882_3885dupAGAC, p.(Ser1296ArgfsTer5) N.i. Heterozygous #148050
KBG syndrome (AD)
Likely Pathogenic
Four SNVs detected with HPO terms-generated in silico gene panel
 RD_P427 NDD, hypotonia, dysmorphic features TBCK, NM_033115, c.469+1G>A;469+1G>A Paternal/
Homozygous #616900
Infantile hypotonia with psychomotor retardation and characteristic facies 3 (AR)
 RD_P428 Arthrogryposis, dysmorphic features ECEL1, NM_004826, c.494T>C, p.(Leu165Pro)
ECEL1, NM_004826, c.2228G>T, p.(Arg743Met)
Not maternal Compound heterozygous #615065
Distal arthrogryposis type 5D (AR)
 RD_P429 Hypotonia,
hearing loss
ACOX1, NM_004035, c.1729-1G>A Paternal/Maternal Homozygous #264470
Peroxisomal acyl-CoA oxidase deficiency (AR)
Likely pathogenic
 RD_P430 Hypertrophic cardiomyopathy, severe anemia, respiratory failure SPTA1, NM_003126, c.83G>A, p.(Arg28His)
SPTA1, NM_003126, c.47854delG, p.(Arg1595Lysfs*38)
Paternal Compound heterozygous #270970
Spherocytosis type 3 (AR)
Repeat expansions detected by WGS
 RD_P431 Hypotonia, ASD, metabolic acidosis ATXN7, STR N.i. Heterozygous #164500
Spinocerebellar ataxia 7 (AD)
Uniparental isodisomy validated by WGS
 RD_P432 Hypotonia, dysmorphic features Maternal UPD 15 (isodisomy) N.a. N.a. #176270
Prader-Willi syndrome (AD)
  1. CNV copy number variant, CMA chromosomal microarray, NDD neurodevelopmental delay, WGS whole-genome sequencing, VUS variant of uncertain significance, SNV single nucleotide variant, STR short tandem repeat, N.i. no information, UPD uniparental disomy, N.a. not applicable, AD autosomal dominant, AR autosomal recessive