TABLE 1.
Causal variants detected by WGS in patients with syndromic SCS.
| Patient no. (gender) | Suture pattern | Phenotype (clinically suspected diagnosis) | Analyses prior to inclusion in the study (on both clinical and research bases) | Gene(transcript)/Chromosomal aberration | Variant annotation - cDNA, protein level/genomic position for CNVs (size) | Variant classification according to ACMG criteria (novelty, zygosity, inheritance, molecular aspects a ) | Detection by screening method | Associated phenotype/disorder (OMIM, PubMed - PMID) | ||
|---|---|---|---|---|---|---|---|---|---|---|
| In silico panel on WGS/WES (133 genes) | HPO-term analysis with Moon/Alissa software | CNV analysis (Alissa + IGV) | ||||||||
| P2603_144 b , c (M) | Bicoronal | SCS (Noonan, Loeys-Dietz, Baraitser-Winter, BPES, Ohdo-like) | SNP-array, targeted NGS panels (Noonan, Marfan, CS-63 genes), WES Trio | KIAA0586 (TALPID3) NM_001329943.2 | c.392delG, p. (Arg131Lysfs*4) | Pathogenic (compound het, maternal) 0.6207% (773 het) and 0.0016059% (2 hom) in gnomAD, truncating frameshift, reported as pathogenic by several sources in the literature and databases, such as ClinVar (VCV000204593.49) and HGMD (CD155358) | — | + (only Moon) | — | Joubert syndrome 23, Autosomal recessive (#616490) |
| c.887A>G, p. (Tyr296Cys) | Likely pathogenic d (novel) (compound het, paternal) 0.0064241% (8) in gnomAD, missense, highly conserved, large physicochemical difference, in trans with pathogenic variant | |||||||||
| P2605_115(M) | Sagittal + lambdoid (Mercedes synostosis) | SCS (Catel-Manzke-like face) | Targeted Sanger (FGFR, TWIST, POR) and NGS panel (63 genes) | YY1 NM_003403.4 | c.1057T>C, p. (Phe353Leu) | Likely pathogenic e (het, expected de novo, absent in the mother, father unavailable) Absent from gnomAD, missense in protein domain, highly conserved, small physicochemical difference, 4/4 damaging, possible splice effect, recently reported as likely pathogenic in ClinVar (VCV002413123.4) | + | + | — | Gabriele-de Vries syndrome (#617557) |
| P2605_105 c (F) | Unicoronal right | SCS (Saethre-Chotzen) | Targeted Sanger (FGFR, TWIST, POR) and NGS-panel (63 genes) | TWIST 1 | Whole-gene deletion (including FERD3L) arr [GRCh37] 7p21.1 (19066802_19662813)x1 (596 kb) f | Pathogenic (het, de novo) | + | + | + | Saethre-Chotzen syndrome (#101400) |
| P2605_102 (M) | Bicoronal + metopic + sagittal (?) | SCS (Shprintzen-Goldberg-like, atypical) | Targeted NGS panel (63 genes) | KAT6A NM_006766.5 | c.3055C>T, p. (Arg1019*) | Pathogenic e (het, expected de novo) Absent in gnomAD, truncating frameshift, possible splice effect, reported as de novo pathogenic in ClinVar (VCV000489088.3) and HGMD (CM194936) | + | + | — | Arboleda-Tham syndrome (#616268) |
| P2605_132 c , g (F) | Unicoronal right | SCS (Saetre-Chotzen-like, Branchiootic – like) | Targeted Sanger (FGFR1, FGFR2, FGFR3, TWIST1) and NGS panel (63 genes) | HDAC9 | Whole-gene deletion (including PRPS1L1, SNX13) arr [GRCh37] 7p21.1 (17930686_19059254)x1 (1,128 kb) f | Likely pathogenic (novel) (het, de novo) Absent from gnomAD | + | — | + | Branchiootic-syndrome (BOS)-like phenotype (PMID: 35710300) |
| P2605_175 c (F) | Unicoronal right | SCS (Saethre-Chotzen-like) | Targeted Sanger (FGFRs, TWIST1, POR), NGS panel (63 genes) | Complex structural rearrangement: Dup2p25 (1.5 Mb) + Del2q22 (3,4 Mb) h | arr [GRCh37] 2p25.2p25.1 (5689487_7379378)x3 (1,7 Mbp) arr [GRCh37] 2q22.1 (138458639_141918297)x1 (3,4 Mbp) | Likely pathogenic (novel) (het, de novo) | — | — | + | Candidate genes for the phenotype: Dup2p25.2:SOX11 (#615866, AD) Del2q22.1: HNMT (#616739,AR, no other variant detected)+LRP1B (*608766)+NXPH2 (*604635) |
| P_1 c (F) | Bicoronal | SCS | In silico panel WGS (29 genes)+MLPA | TCF12 NM_207036.1 | c.1746-8T>G, p. (Ser583Phefs*5) | Likely pathogenic (novel) (het, de novo) Absent from gnomAD, high probability of splice-effect confirmed by mRNA/cDNA analysis | + | + | — | Craniosynostosis 3 (#615314) |
| P_2 b , c (F) | Sagittal | SCS | HaloPlex NGS-panel (12 genes)+MLPA | Duplication 22q13.1-q13.2 | arr [GRCh37] 22q13.1q13.2 (40545592_42096995)x3 (1.55 Mb) f | Likely pathogenic (novel) (het, de novo) | — | + (only Moon) | + | Chromosome 22q13 duplication syndrome (#615538) Candidate gene for the phenotype: EP300 |
| P_3 c (F) | Bicoronal + lambdoid (?) | SCS (Apert, typical) | In silico panel on WGS (29 genes) + MLPA | FGFR2 NM_000141.5 | c.940-19_c.940-18insAlu | Likely pathogenic (novel) (het, de novo) Absent in gnomAD, Alu-insertion of 18 basepairs upstream from the intron 7 – exon 8 boundary, possibly affecting splicing, previously reported Alu-insertions impacted splicing | — | — | + | Apert syndrome (#101200) |
| P_4 (M) g | Sagittal | SCS | SNP-array, Fragile X, in silico panel WGS (29 genes)+MLPA | FOXP1 NM_001349338.3 | c.910G>T, p. (Gly304*) | Pathogenic (novel) (het, de novo) Absent from gnomAD, truncating, similar LoF variants reported as pathogenic | — | + (only Moon) | — | Intellectual developmental disorder with language impairment with or without autistic features (# 613670) |
| P_5 (F) g | Sagittal | SCS (Crouzon, atypical) | In silico panel WGS (29 genes)+MLPA | NSD2 (WHSC1) NM_133330.3 | Ex 1–8 deletion arr [GRCh37] 4p16.3 (1877218_1934173)x1 (57 kb) i | Likely pathogenic (novel) (het, de novo) | - | + (only Moon) | + | Rauch-Steindl syndrome (# 619695) |
Genotype frequency in control population (gnomAD), effect at protein level, location in protein domain, nucleotide/amino acid evolutionary conservation, physiochemical difference between amino acids, no/4 – number of in silico prediction programs assessing the variant as damaging/tolerated per total number of programs (4): SIFT, MutationTaster, PolyPhen-2: HumDiv and HumVar.
Parental samples were available for WGS, trio analysis.
Secondary findings with potentially modulator effect (Supplementary Table S2).
Considerations for the variant classification: compound heterozygosity with a pathogenic variant and the genotype–phenotype correlation.
Considerations for the variant classification: expected de novo occurrence, previous report with de novo occurrence, and the genotype–phenotype correlation.
Structural variant confirmed by MLPA., the breakpoints were manually curated, the array annotation is suggested by the variant interpretation program.
Confirmed by microarray (Affymetrix CytoScan HD). Parental samples were analyzed using both microarray and karyotyping in order to exclude a balanced structural rearrangement.
Additional discarded variants due to their unlikelihood to contribute to the phenotype (Supplementary Table S5).
The breakpoints were manually curated. Parental samples were analyzed with microarray (no MLPA, kit available).
(−) variant not detected by method; (+) variant detected by method; BOS, Branchiootic syndrome; BPES, Blepharophimosis, epicanthus inversus, and ptosis syndrome; ClinVar, Clinical Genome Resource (database of variants associated with human disease); F, female; gnomAD, The Genome Aggregation Database; het, heterozygous; HGMD, Human Gene Mutation Database; LoF, loss-of-function; M, male; MLPA, multiplex ligation-dependent probe amplification; VUS, variant of uncertain significance.