Table 1.
Patient Characteristic and Clinical Features
| Patient | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
|---|---|---|---|---|---|---|---|---|
| Variant | c.143 | c.143 | c.248G> | c.329 | c.329G> | 586 | 589 | 607+2 |
| G>A’ | G>A’ | A’ | G>A’ | A’ | A>G’ | G>A’ | DELT* | |
| Protein Change | p.(Gly48Glu) | p.(Gly48Glu) | p.(Arg83His) | p.(Gly110Asp) | p.(Gly110Asp) | p.(Met196Val) | p.(Ala1977Thr) | p.(E202_G203insGKWQXY) (Splicing Effect: Use Of A Later Donor Site) |
| Variant classification ACMG** | 3 | 4 | 3 | 4 | 5 | 3 | 3 | 4 |
| Inheritance | De Novo | De Novo | De Novo | De Novo | De Novo | De Novo | De Novo | De Novo |
| Phenotype | CSCF | CSCF | CSCF | CSCF | CSCF | CSCF | CSCF | CSCF |
| Age | 5 | 0 | 3 | 6 | 15 | 8 | 1 | 12 |
| In Years | (8 Months) | |||||||
| Gender | Female | Male | Female | Female | Female | Male | Female | Female |
| Ancestry | Caucasian | American/Caucasian | Hispanic | Caucasian | Caucasian | Caucasian/Asian | Middle‐East | Caucasian |
| Country Of Participation | Holland | USA | Holland | Holland | Holland | Holland | Holland | England |
| Postnatal measurements | ||||||||
| Weeks Of Gestation | 39 3/7 | 37 | 38 | 38 6/7 | 40 | 38 2/7 | 39 | 41 |
| Weight, Gr (SDS) | 2740 (‐2) | 3.5 () | 2850 (0) | 3052 (0) | 2340 (<‐2.5) | 3060 (‐0.5) | 3200 (0) | 3044 (‐1) |
| Length, Cm (SDS) | 47 (‐1,4) | 49 (‐4.0) | 46 (‐1.9) | 48 (0) | ||||
| Head Circumference, Cm (SDS) | 33 (‐1,6) | 34 (‐1.7) | 35.5 (+0.7) | 35 (0 SD) | ||||
| Measurements Last Evaluation | ||||||||
| Weight, Kg | 14.2 | 8.9 | 12 | 17 | 36.6 | 21,2 | 9,95 | 29.6 |
| Length, Cm (SDS) | 102 (‐2.7) | 66 (‐1.68) | 86,7 (‐3) | 104 (‐3,1) | 153,2 (‐2,1) | 122 (‐2,1) | 73.8 (‐1.4) | 143 (<‐2.5) |
| Head Circumference, Cm (SDS) | 48 (‐1.7) | 43.6 (‐0.74) | 49,2 (0) | 50 (‐0,6) | 53,4 (‐0.9) | 52 (‐0,3) | 48.2 (1.1) | 51,5 (‐1,4) |
| Facial | ||||||||
| Low Posterior Hair Line | Yes | No | No | Yes | No | No | ||
| Hypotonic Face | Yes | Yes | No | No | Yes | Yes | No | No |
| Full Cheeks | Yes | Yes | Yes | Yes | No | Yes | Yes | No |
| Low‐Set Ears | No | Yes | No | Yes | No | Yes | Yes | |
| Posteriorly Rotated Ears | Yes | Yes | No | Yes | Yes | Yes | No | Yes |
| Hypertelorism | Yes | Yes | No | Yes | No | Yes | Yes | Yes |
| Triangular Face | Yes | No | No | No | No | No | Yes | No |
| Strabismus | Yes | No | No | No | Yes | Yes | No | No |
| Ptosis | Yes | Yes | No | No | Yes | Yes | No | Yes |
| Downslanting Palpebral Fissures | No | No | No | No | No | No | No | Yes |
| Upslanting Palpebral Fissures | Yes | Yes | No | No | No | Yes | No | No |
| Epicanthal Folds | Yes | Yes | Yes | No | No | Yes | No | Yes |
| Peri‐Orbital Fullness | Yes | Yes | No | No | No | Yes | Yes | No |
| Anteverted Nares | Yes | Yes | Yes | No | Yes | No | Yes | |
| Round Tipped Nose | Yes | Yes | Yes | Yes | Yes | Yes | Yes | |
| Long Philtrum | Yes | Yes | Yes | No | Yes | Yes | Yes | |
| High Arched Palate | No | Yes | Yes | No | Yes | |||
| Micrognathia | No | Yes | Yes | No | No | Yes | No | No |
| Webbed Neck | Yes | Yes | No | No | No | No | No | |
| Cardiac Phenotype | ||||||||
| Congenital Heart Defect | Yes | No | No | Yes | Yes | No | Yes | |
| Ventricular Septal Defects | No | No | No | No | No | No | ||
| Atrial Septal Defects | No | No | No | No | No | No | Yes | |
| Cardiomyopathy | No | Yes | No | Yes | No | No | No | |
| Other | Dilated Cardiomyopathy with right ventricular dysfunction. He is on the waiting list for Heart Transplantation | Dilated Cardiomyopathy | Bowing Mitral Valve without Regurgitation, PDA | |||||
| Skeletal Phenotype | ||||||||
| Joint Laxity | Yes | No | Yes | Yes | Yes | Yes | Yes | |
| Scoliosis | No | No | No | No | Yes (35 Degrees) | No | No | Yes |
| Vertebral Abnormalities | Yes | No | Yes | Yes | ||||
| Carpal Fusion | Yes | No | No | No | No | Yes | ||
| Flexion Contractures | No | No | No | No | No | |||
| Brachydactyly | Yes | No | No | Yes | Yes | Yes | Yes | |
| Camptodactyly | No | No | No | No | No | |||
| Pectus Excavatum | Yes | No | No | No | No | No | No | |
| Neurologic Phenotype | ||||||||
| Hypotonia | Yes | No | Yes | No | Yes | Yes | ||
| Atrophic Adductor Pollicis | Yes | No | Yes | Yes | ||||
| Muscle Hypoplasia (Other) | No | No | ||||||
| Intellectual Disability | No | No | No | No | No | No | ||
| Behavior Disorders | No | Yes (Autism) | No | No | ||||
| MRI Brain | Left Hemispheric Ischemic Lesions At Insulo‐Parieto‐ And Temporal Region That Corresponds To MCA Territory. Thin Corpus Callosum, Chiari I Malformation | Wide Virchow‐Robin Space, Some Hyperintensity, In Particular Occipital In The White Matter. Slightly Broadened Front Horns. | Normal At Age 3 Weeks | |||||
| Miscellaneous | ||||||||
| Hearing Loss | No | No | No | Yes (Conductive) | No | Yes (Sensorineural) | ||
| Feeding Difficulties In Infancy | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes |
| Cryptorchidism | ‐ | No | ‐ | ‐ | ‐ | Yes | ‐ | ‐ |
| Widely Spaced Nipples | Yes | Yes | No | Yes | Yes | Yes | ||
| Other | Hypogamma‐globulinemia, Eczema | Hirsutism And Deep Sacral Dimple | Rhizomelic Shortening | Class 3 malocclusion jaw |
| Patient | 9 | 10 (Father P9) | 11 | 12 | 13 | 14 | 15 | 16 | Total |
|---|---|---|---|---|---|---|---|---|---|
| Variant | 616 | 616 | 617 | 713 | 721 | 721 | 337 | 1535 | |
| T>G’ | T>G’ | A>G’ | G>A’ | T>G’ | T>G’ | T>G’ | C>T’ | ||
| Protein Change | p.(Tyr206Asp) | p.(Tyr206Asp) | p.(Tyr206Cys) | p.(Arg238Gln) | p.(Trp241Gly) | p.(Trp241Gly) | p.(Tyr113Asp) | p.(Pro485Leu) | |
| Variant classification ACMG** | 4 | 4 | 4 | 4 | 5 | 5 | 3 | 4 | |
| Inheritance | Paternal | Na | De Novo | De Novo | De Novo | Not maternal; | De Novo | De Novo | 1 Inherited (1 father not tested) |
| Phenotype | CSCF | CSCF | CSCF | CSCF | CSCF | CSCF | FMD2 | FMD2 | 2/15 FMD2 |
| Age | 0 | 35 | 9 | 7 | 2 | 36 | 18 | 4 | Median 6 |
| In Years | (2 Months) | Iqr 10 | |||||||
| Gender | Female | Male | Male | Female | Female | Female | Male | Female | 10/15 Female |
| Ancestry | Caucasian/Asian | Caucasian | Caucasian | Caucasian | Caucasian | Chinese | Caucasian | Caucasian | 10/15 Caucasian |
| Country Of Participation | Holland | Holland | USA | Switzerland | England | USA | Holland | Italy | 8/15 Holland |
| Postnatal measurements | |||||||||
| Weeks Of Gestation | 37 5/7 | 40 2/7 | 38 4/7 | 36 2/7 | Term | 34 1/7 | 35 2/7 | 3 Born Premature | |
| Weight, Gr (SDS) | 2800 (‐1) | 3730 (‐0.5) | 2570 (‐1.9) | 2003 (‐2.5) | 2700 (‐2 SDS) | 1655 (<‐2.5) | 1910 (‐2.5) | 4 SGA | |
| Length, Cm (SDS) | 45 (‐1) | 50 (‐1) | 48 (‐1.4) | 41,9 (‐2.2) | 42 (‐1) | Overall Normal | |||
| Head Circumference, Cm (SDS) | 34 (+1) | 35 (+1.9) | 34.5 (+2) | 32,5 (+1) | 28,5 (‐2.5) | Broad Range | |||
| Measurements Last Evaluation | |||||||||
| Weight, Kg | 4,2 | 18 | 21 | 10.6 | 37.8 | 47,8 | 12.5 | ||
| Length, Cm (SDS) | 53 (‐1,6) | 162,5 (‐3) | 115.2 (‐3.2) | 120.9 (‐0.8) | 81.3 (‐1.3) | 146.3 (<‐2.5) | 165,1 (‐2,2) | 88 (‐3,1) | 11/16 Short Stature |
| Head Circumference, Cm (SDS) | 37 (‐1) | 55,5 (‐1,1) | 50 (‐1.8) | 53.6 (1.3) | 48 (0.3) | 45 (<‐2.5) | 1/14 Microcephalic, FMD2 patient | ||
| Facial | |||||||||
| Low Posterior Hair Line | No | No | No | No | 2/10 | ||||
| Hypotonic Face | No | No | Yes | No | No | Yes | 6/14 | ||
| Full Cheeks | Yes | No | Yes | Yes | No | Yes | Yes | 11/15 | |
| Low‐Set Ears | Yes | No | No | No | No | 5/12 | |||
| Posteriorly Rotated Ears | No | No | No | No | No | No | 6/14 | ||
| Hypertelorism | Yes | Yes | No | No | Yes | Yes | 10/14 | ||
| Triangular Face | No | Yes | No | No | No | 3/13 | |||
| Strabismus | No | No | No | No | 3/12 | ||||
| Ptosis | No | Yes | Yes | No | Yes | No | Yes | 9/15 | |
| Downslanting Palpebral Fissures | No | Yes | Yes | No | No | Yes | 4/14 | ||
| Upslanting Palpebral Fissures | No | No | No | No | No | No | 3/14 | ||
| Epicanthal Folds | No | No | Yes | Yes | Yes | 8/13 | |||
| Peri‐Orbital Fullness | Yes | Yes | No | Yes | 7/12 | ||||
| Anteverted Nares | No | No | Yes | Yes | No | No | 7/13 | ||
| Round Tipped Nose | No | Yes | Yes | Yes | No | 10/12 | |||
| Long Philtrum | No | Yes | No | No | 7/11 | ||||
| High Arched Palate | Yes | No | Yes | Yes | 6/9 | ||||
| Micrognathia | No | No | No | No | Yes | Yes | 5/14 | ||
| Webbed Neck | No | No | Yes | No | No | 3/12 | |||
| Cardiac Phenotype | |||||||||
| Congenital Heart Defect | Yes | No | Yes | Yes | No | No | Yes | Yes | 9/15 |
| Ventricular Septal Defects | No | No | No | No | Yes | Yes | 2/12 | ||
| Atrial Septal Defects | No | No | No | No | No | No | 1/13 | ||
| Cardiomyopathy | Yes | No | No | No | Yes | No | No | 4/14 | |
| Other | Hypertrophic Cardiomyopathy | Aortic Atresia, Hypoplastic Left Heart Syndrome | Mitral Valve Prolapse | Dilated cardiomyopathy, SVT with ablation age 35, mid‐moderate tricuspid regurgitation | PDA | PDA, Bicuspid Aortic Valve With Stenosis, PLSCV, Single Coronary Sinus, Ectopic Atrial Tachycardia | |||
| Skeletal Phenotype | |||||||||
| Joint Laxity | Yes | No | Yes | 8/11 | |||||
| Scoliosis | No | Yes | Yes | 4/11 | |||||
| Vertebral Abnormalities | Yes | No | Yes | 5/7 | |||||
| Carpal Fusion | No | No | No | 2/8 | |||||
| Flexion Contractures | No | No | Yes | Yes | 2/9 (Both Fmd2) | ||||
| Brachydactyly | Yes | No | Yes | 7/10 | |||||
| Camptodactyly | No | Yes | Yes | 2/8 (Both Fmd2) | |||||
| Pectus Excavatum | No | Yes | Yes | No | 3/11 | ||||
| Neurologic Phenotype | |||||||||
| Hypotonia | Yes | Yes | Yes | No | Yes | 8/11 | |||
| Atrophic Adductor Pollicis | No | No | Yes | 4/7 | |||||
| Muscle Hypoplasia (Other) | Yes (Right Pectoralis) | Yes (Hands) | Yes | 3/5 | |||||
| Intellectual Disability | No | No | No | No | Yes (Severe) | 1/11 (Fmd2) | |||
| Behavior Disorders | Yes (Autism) | Yes (Autism, Phobias, Pica) | No | 3/7 | |||||
| MRI Brain | Scattered Small Foci Of Restricted Diffusion | Cerebral Atrophy, Reduced Corpus Callosum, And Chiari 1 Malformation | |||||||
| In The Periventricular White Matter Including Lesions | |||||||||
| In Bilateral Parietal White Matter And A Single Lesion Within The Left | |||||||||
| Frontal White Matter. Most Suggestive Of White | |||||||||
| Matter Hypoxic Ischemic Injury. | |||||||||
| Miscellaneous | |||||||||
| Hearing Loss | No | Yes (Conductive) | Yes (Conductive) | Yes | Yes (Mixed) | No | 6/12 | ||
| Feeding Difficulties In Infancy | Yes | Yes | Yes | No | Yes | 11/13 | |||
| Cryptorchidism | ‐ | No | No | ‐ | ‐ | Yes | ‐ | 2/5 | |
| Widely Spaced Nipples | No | Yes | Yes | Yes | 8/10 | ||||
| Other | Short Arms | Urethral meatus slit‐like orifice positioned inferiorly on the glans penis | Myopia ‐11 diopter | Ambiguous Genitalia | Severe Eczema |
‐ = Not Applicable; Empty= Not Available, CSCF = Cardiospondylocarpofacial Syndrome, FMD2 = Frontometaphyseal Dysplasia Type 2, IQR = Interquartile Range, SGA = Small for Gestational Age, PDA = Patent Ductus Arteriosus, PLSCV = Persistent Left Superior Vena Cava
‘Complying with HGSV format and reference sequence NM_145331.2.
*
Complying with HGSV format and reference sequence NC_000006.12 (NM_003188.3).
**
Richard et al. 2015. Genet Med. doi: 10.1038/gim.2015.30