Table 1

Clinical and genetic characteristics of probands with biallelic variants in SMAD6

This study
Proband 1
This study
Proband 2
Kloth et al, 2019
Proband 1
Kloth et al, 2019
Proband 2
GenotypeHomozygousHomozygousHomozygousCompound heterozygous
Chromosomal position (hg38)chr15:66703842T>G; chr15:66703842T>Gchr15: 66 704 075G>A; chr15: 66 704 075G>Achr15: 67073779T>C; chr15: 67073779T>Cchr15: 67073451T>A; chr15: 67073829T>C
Nucleotide changec.584T>G; c.584T>Gc.817G>A; c.817G>Ac.1397T>C; c.1397T>Cc.1069T>A; c.1447T>C
Protein changep.(Val195Gly); p.(Val195Gly)p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)])p.(Ile466Thr); p.(Ile466Thr)p.(Phe357Ile);
TypeMissenseMissense/splice-siteMissenseMissense; missense
Protein domainMH1MH1MH2MH2; MH2
CADD score (v1.6)313528.831; 28.9
gnomAD (v2.1.1)AbsentAbsentAbsentAbsent
Family historyHealthy parentsHealthy parentsHealthy parentsHealthy parents
Age at last follow-upEarly childhoodEarly childhoodMiddle childhoodMiddle childhood
CraniosynostosisMetopic synostosisMetopic synostosisAbsentAbsent
Global developmental delayYesNoYes No
Gross motor delayYesNoSlightly delayed No
Speech delayYesNoSlightly impaired§ No
Cardiac and outflow tract abnormalitiesNoNoCoarctation of the aortaDysplastic pulmonary valve, pulmonic stenosis, coronary artery stenosis (ie, left main coronary artery), pulmonary artery stenosis, dilated cardiomyopathy
Radioulnar synostosisLeft-sidedBilateralBilateralAbsent
OtherCryptorchidism, abnormal pulmonary vein morphology, factor XI deficiency, astigmatismNoneFacial dysmorphism (eg, microcephaly, abnormality of the ears, etc), unilateral renal hypoplasia, toe syndactyly (bilateral), dorsal hirsutism, EEG¶ abnormalityFacial dysmorphism (eg, low anterior hairline, prominent nose, short neck, abnormality of the ears, etc), transient neutropenia, decreased circulating antibody level
  • Reference build, GRCh38; RefSeq NM_005585.5.

  • Human Phenotype Ontology (HPO) terms have been used to annotate the phenotypes mentioned in the table.

  • *Also associated with abnormal (p.(Glu273Serfs*72)) splicing, see text and figure 1C,D.

  • †With intellectual disability.

  • ‡Sitting at 8 months, crawling at 10 months, walking at 19 months.

  • §Speaks 3–4 word sentences, uses fantasy language.

  • ¶EEG, electroencephalography.