Genotypes and phenotypes of affected individuals carrying rare germ line MECOM variants
| Patient ID . | cDNA (NM_004991.4) . | Protein (NP_004982.2) . | Sex . | Age at presentation . | HSCT (age) . | Somatic genetic rescue . | Additional somatic genetic changes . | Hematopoietic abnormalities (age at diagnosis) . | Skeletal abnormalities . | Cardiac/vascular abnormalities . | Other abnormalities . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1-I-2 | c.2577+4A>T | p.(Arg830Serfs∗21) p.(Val831Cysfs∗11) | F | 15 y | Haploidentical HSCT (36 y) | Not detected | None detected | Pancytopenia and anemia (15 y) | Short stature, brachydactyly, short toe, proximal placement of hallux, short proximal phalanx of hallux, short proximal phalanx of fifth finger, and cholelithiasis | Ventricular septal defect | |
| 1-II-5 | c.2577+4A>T | p.(Arg830Serfs∗21) p.(Val831Cysfs∗11) | F | In utero | NA | N | Not analyzed | Aplasia with dysplastic features (in utero) | Preaxial polydactyly, supernumerary ribs, and coronal cleft vertebrae | None reported | Fetal Hydrops, splenic hemosiderin deposition, and small placenta |
| 2-II-6 | c. 1174delT | p.(Cys392Alafs∗29) | F | 9 mo | N | Not detected | None detected |
| Not present | Mild aortic root dilatation | Congenital hearing loss |
| 3-II-4 | c.2873_2875delTTA | p.(Phe958_Ser959del insCys) | M | Birth | N | cnLOH chr3q | Transient del(20q) |
| Proximal RUS, hypoplastic thumbs, short, broad fingers, short fifth digits, and coalition of right capitate and hamate, and bilateral absent patellae | Mild mitral valve prolapse | |
| 4-II-4 | c.816dupT | p.(Pro273Serfs∗2) | M | Birth | N | cnLOH chr3q | Transient del(20q) ASXL1 p.(Arg860Glufs∗7) ASXL1 p.(Leu775∗) |
| Club foot and small patellae | Aortic root dilatation progressing to aortic aneurysm and mitral valve defect | |
| 4-II-1 | c.816dupT | p.(Pro273Serfs∗2) | F | 59 y | N | Not detected | DNMT3A p.(Leu504Trpfs∗147) ETV6 p.(Ser139Tyrfs∗14) TET2 p.(Cys973∗) TP53 p.(Ala276Asp) |
| Small patellae | Aortic root dilatation | Bicornuate uterus, mild sensorineural hearing loss, cataract (50 y), and bilateral scarring of kidneys with normal function |
| 5-II-1 | c.2889C>G | p.(Asn963Lys) | F | Childhood (exact age unknown) | N | cnLOH chr3q | ASXL1 p.(Gly646Trpfs∗12) SETBP1 p.(Ser869Asn) EZH2 p.(Tyr733Phe) EZH2 p.(Cys609_Ser610delinsTyr) ETV6 p.(Arg369Trp) |
| Clinodactyly in fingers and toes | None reported | Hearing impairment, locally recurrent anal squamous cell carcinoma, gynecological warts, cataracts, and glaucoma |
| 6-I-1 | c.2905C>T | p.(Arg969Cys) | M | 4 y | N | Not detected | Not analyzed | No abnormalities | Bilateral RUS-surgically corrected at age 4 | None reported | |
| 6-II-1 | c.2905C>T | p.(Arg969Cys) | M | 2 y | N | Not detected | Not analyzed | No abnormalities | Bilateral RUS and clubfeet | Small patent ductus arteriosus/patent foramen ovale, hemodynamically not significant | Slightly cupped ears with borderline normal hearing |
| Patient 7 | c.2813G>A | p.(Arg938Gln) | M | 34 y | N | Y | None detected |
| Presumed bilateral RUS (limited ability to pronate arms bilaterally), bilateral club foot, Perthes-like hip disease, endochondromata, and ecchondromata | None | Small kidneys without structural deficits, nonspecific punctate foci of T2/FLAIR hyperintensity in the peripheral/subcortical white matter slightly greater than expected for patient's age |
| Patient 8 | c.2776T>C | p.(Cys926Arg) | F | 27 y | N | Not detected | Not analyzed | Severe thrombocytopenia and mild leukopenia | Clinodactyly of the thumb, short toe, unfused vertebral arch L5, coxa valga, and cam deformity | None reported | |
| Patient 9 | c.3106C>T | p.(Arg1036∗) | M | 19 y | N | Not detected | Not analyzed | Thrombocytopenia | Marfanoid habitus, tall spindly fingers, hypoplastic thumbs, and adducted toes | None reported | |
| Patient 10 | c.1696G>T | p.(Glu566∗) | F | Birth | MUD (11 mo) | Not detected | Not analyzed |
| Retrognathia | Patent foramen ovale and pulmonary branch stenosis (resolved without intervention at 2 y) | Congenital conductive hearing in loss both ears, with cleft palate (corrected at 7 mo) |
| Patient 11 | c.2813G>A | p.(Arg938Gln) | F | 17 y | N | Y | Not analyzed |
| Right-sided RUS, camptodactyly of the fifth fingers, brachydactyly of the first toes, and scoliosis | Bicuspid aortic valve | Congenital mixed hearing loss, bilateral relatively small kidneys without structural defects, from age 18 onwards, chronic mild renal insufficiency (stage 2) |
| Patient 12 | Complete loss of MECOM gene | F | In utero | N | N | Not analyzed | Hypocellular bone marrow | Micrognathia | At autopsy: ductus arteriosus type II with VSD. Pericardial fluid and ascites | Generalized edema hygroma colli nuchal translucency cleft palate, simple ears, lung hypoplasia due to pleural fluid, and unilateral renal agenesis |
| Patient ID . | cDNA (NM_004991.4) . | Protein (NP_004982.2) . | Sex . | Age at presentation . | HSCT (age) . | Somatic genetic rescue . | Additional somatic genetic changes . | Hematopoietic abnormalities (age at diagnosis) . | Skeletal abnormalities . | Cardiac/vascular abnormalities . | Other abnormalities . |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1-I-2 | c.2577+4A>T | p.(Arg830Serfs∗21) p.(Val831Cysfs∗11) | F | 15 y | Haploidentical HSCT (36 y) | Not detected | None detected | Pancytopenia and anemia (15 y) | Short stature, brachydactyly, short toe, proximal placement of hallux, short proximal phalanx of hallux, short proximal phalanx of fifth finger, and cholelithiasis | Ventricular septal defect | |
| 1-II-5 | c.2577+4A>T | p.(Arg830Serfs∗21) p.(Val831Cysfs∗11) | F | In utero | NA | N | Not analyzed | Aplasia with dysplastic features (in utero) | Preaxial polydactyly, supernumerary ribs, and coronal cleft vertebrae | None reported | Fetal Hydrops, splenic hemosiderin deposition, and small placenta |
| 2-II-6 | c. 1174delT | p.(Cys392Alafs∗29) | F | 9 mo | N | Not detected | None detected |
| Not present | Mild aortic root dilatation | Congenital hearing loss |
| 3-II-4 | c.2873_2875delTTA | p.(Phe958_Ser959del insCys) | M | Birth | N | cnLOH chr3q | Transient del(20q) |
| Proximal RUS, hypoplastic thumbs, short, broad fingers, short fifth digits, and coalition of right capitate and hamate, and bilateral absent patellae | Mild mitral valve prolapse | |
| 4-II-4 | c.816dupT | p.(Pro273Serfs∗2) | M | Birth | N | cnLOH chr3q | Transient del(20q) ASXL1 p.(Arg860Glufs∗7) ASXL1 p.(Leu775∗) |
| Club foot and small patellae | Aortic root dilatation progressing to aortic aneurysm and mitral valve defect | |
| 4-II-1 | c.816dupT | p.(Pro273Serfs∗2) | F | 59 y | N | Not detected | DNMT3A p.(Leu504Trpfs∗147) ETV6 p.(Ser139Tyrfs∗14) TET2 p.(Cys973∗) TP53 p.(Ala276Asp) |
| Small patellae | Aortic root dilatation | Bicornuate uterus, mild sensorineural hearing loss, cataract (50 y), and bilateral scarring of kidneys with normal function |
| 5-II-1 | c.2889C>G | p.(Asn963Lys) | F | Childhood (exact age unknown) | N | cnLOH chr3q | ASXL1 p.(Gly646Trpfs∗12) SETBP1 p.(Ser869Asn) EZH2 p.(Tyr733Phe) EZH2 p.(Cys609_Ser610delinsTyr) ETV6 p.(Arg369Trp) |
| Clinodactyly in fingers and toes | None reported | Hearing impairment, locally recurrent anal squamous cell carcinoma, gynecological warts, cataracts, and glaucoma |
| 6-I-1 | c.2905C>T | p.(Arg969Cys) | M | 4 y | N | Not detected | Not analyzed | No abnormalities | Bilateral RUS-surgically corrected at age 4 | None reported | |
| 6-II-1 | c.2905C>T | p.(Arg969Cys) | M | 2 y | N | Not detected | Not analyzed | No abnormalities | Bilateral RUS and clubfeet | Small patent ductus arteriosus/patent foramen ovale, hemodynamically not significant | Slightly cupped ears with borderline normal hearing |
| Patient 7 | c.2813G>A | p.(Arg938Gln) | M | 34 y | N | Y | None detected |
| Presumed bilateral RUS (limited ability to pronate arms bilaterally), bilateral club foot, Perthes-like hip disease, endochondromata, and ecchondromata | None | Small kidneys without structural deficits, nonspecific punctate foci of T2/FLAIR hyperintensity in the peripheral/subcortical white matter slightly greater than expected for patient's age |
| Patient 8 | c.2776T>C | p.(Cys926Arg) | F | 27 y | N | Not detected | Not analyzed | Severe thrombocytopenia and mild leukopenia | Clinodactyly of the thumb, short toe, unfused vertebral arch L5, coxa valga, and cam deformity | None reported | |
| Patient 9 | c.3106C>T | p.(Arg1036∗) | M | 19 y | N | Not detected | Not analyzed | Thrombocytopenia | Marfanoid habitus, tall spindly fingers, hypoplastic thumbs, and adducted toes | None reported | |
| Patient 10 | c.1696G>T | p.(Glu566∗) | F | Birth | MUD (11 mo) | Not detected | Not analyzed |
| Retrognathia | Patent foramen ovale and pulmonary branch stenosis (resolved without intervention at 2 y) | Congenital conductive hearing in loss both ears, with cleft palate (corrected at 7 mo) |
| Patient 11 | c.2813G>A | p.(Arg938Gln) | F | 17 y | N | Y | Not analyzed |
| Right-sided RUS, camptodactyly of the fifth fingers, brachydactyly of the first toes, and scoliosis | Bicuspid aortic valve | Congenital mixed hearing loss, bilateral relatively small kidneys without structural defects, from age 18 onwards, chronic mild renal insufficiency (stage 2) |
| Patient 12 | Complete loss of MECOM gene | F | In utero | N | N | Not analyzed | Hypocellular bone marrow | Micrognathia | At autopsy: ductus arteriosus type II with VSD. Pericardial fluid and ascites | Generalized edema hygroma colli nuchal translucency cleft palate, simple ears, lung hypoplasia due to pleural fluid, and unilateral renal agenesis |
F, female; HSCT, haematopoietic stem cell transplant; M, male; MUD, matched unrelated donor; N, no; NA, not applicable; VSD, ventricular septal defect; Y, yes.