Table 1.
Summary of Clinical and Molecular Findings of Affected Individuals
| Clinical features (ethnic origin) | P1 (Egypt) | P2 (Belgium) | P3 (Italy) | P4 (Denmark) | P5 (France) | P6 (France) | P7 (Australia) |
|---|---|---|---|---|---|---|---|
| Age, gender | 33 years, male | 42 years, female | fetus (23 weeks), female | 18 years, female | 15 years, female | 20 years, male | 41 years, female |
| Height | 165 cm (−1.61 SD) | 139 cm (−5 SD); disproportionate short stature | fetus length: 27 cm (<3%) | 163 cm (−1 SD) | 148.5 cm (−1.8 SD) | 175 cm (0 SD) | 165 cm (−0.19 SD) |
| Weight | 97 kg (+1.74 SD) | 61,5 kg (+0.46 SD) | 467 g (25% < p < 50%) | 47.3 kg (−2.8 SD) | 47 kg (−1 SD) | 53 kg (−1.5 SD) | 51.2 kg (−1.03 SD) |
| Head circumference | 57 cm (+1.32 SD) | 52,6 cm (−1.6 SD) | not available | 51 cm (−3 SD) | 55 cm (M) | 56,5 cm (+ 0.5 SD) | 56 cm (+ 1.18 SD) |
| Congenital heart abnormalities | no, but present in the affected offspring of the proband | no, but present in the affected offspring of the proband | yes, AVSD with myocardial hypertrophy | yes, AVSD and left cava superior entering into the coronary sinus | yes, single atrium, mitral anomaly | yes, single atrium, mild mitral valve regurgitation | yes, single atrium, surgically corrected in infancy; atrial fibrillation in adulthood with persistent incompetence of the valves |
| Postaxial polydactyly of the hands | yes, bilateral | yes, bilateral | yes, bilateral | yes, bilateral | yes, bilateral | yes, bilateral | yes, unilateral (right hand) |
| Postaxial polydactyly of the feet | yes, bilateral | no | yes, unilateral (hexadactyly of the left foot) | yes, bilateral | no | yes, bilateral | yes, bilateral |
| Other hands/feet anomalies | brachydactyly | brachydactyly; fusion of hamate and capitate in right hand | not reported | short and broad with shortening of middle and distal phalanges and toes | brachydactyly and large great toe | fifth finger clinodactyly (unilateral) | fifth finger clinodactyly, broad toes, and mild digital clubbing |
| Long trunk | yes | yes, in childhood | not reported | yes | yes, moderate | no | no |
| Narrow thorax | no, but present in the affected offspring of the proband | yes, in childhood | yes, short ribs | yes | yes, moderate | no | no |
| Upper/lower limb shortening | no (arm span 162 cm), but present in the affected offspring of the proband | yes (arm span 121 cm) | micromelia | yes | no | no | no |
| Genu valgum | yes | yes | not available | yes, genu valgum and previous surgery for coxa vara | yes | no | no, but recurrent dislocated patellae |
| Teeth abnormalities | yes, congenitally missing upper lateral incisors bilateral and lower right lateral incisor. Diastema | yes, conical teeth; early decay | not available | small central maxillary incisors, conical right canine, and hypodontia, invagination, agenesis, and supernumerary teeth of lateral mandibular incisors | yes, hypodontia | no | no |
| Nail dysplasia | no, but present in the affected offspring of the proband | yes | not available | yes, especially on the toes, also broad nails on both thumbs | no | no | no |
| Facial/lip abnormalities | long face with mid face hypoplasia, short philtrum, overhanging nasal tip | notched upper lip | not available | long face, short and deep philtrum, tented upper lip | long face | no | broad forehead, hypertelorism, prognathism, prominent nasal tip |
| Multiple frenula or abnormal gum-lip attachment | yes, multiple upper and lower lingual frenula, hypoplastic maxilla with cross bite | multiple oral frenula at lower lip present at birth | not available | yes, abnormal gum-lip attachment | multiple oral frenula at lower lip | no | no |
| Intellectual disability | no | no | not applicable, fetus with brain edema | no, in childhood a period with mild developmental delay including mild language delay, gross motor difficulties, balance problems, and concentration problems; later diagnosed with dyslexia | no | yes, mild intellectual disability, reading and writing acquired, severe anxiety | yes, severe intellectual disability with autistic features. Medically refractory focal epilepsy |
| Neoplastic lesions | absent at age 33 years | absent at age 42 years | not reported | absent at age 18 years | absent at age 15 years | absent at age 20 years | yes, grade 1 borderline mucinous ovarian tumor, liver haemangioma, renal cell carcinoma |
| Clinical diagnosis | WAD | EvC | EvC | EvC | EvC | common atrium and polydactyly | common atrium and polydactyly |
| Affected gene variant description (GRCh37/hg19) |
PRKACA chr19: 14211648 C>T NM_002730.4: c.409 G>A p.Gly137Arg |
PRKACA chr19: 14211648 C>T NM_002730.4: c.409 G>A p.Gly137Arg |
PRKACA chr19: 14211648 C>T NM_002730.4: c.409 G>A p.Gly137Arg |
PRKACB chr1: 84668426 G>C NM_002731.3: c.703G>C p.Gly235Arg |
PRKACB Chr1: 84647935 C>T NM_002731.3: c.161C>T p.Ser54Leu |
PRKACB Chr1: 84649745 A>G NM_002731.3: c.263A>G p.His88Arg |
PRKACB Chr1: 84649744 C>A NM_002731.3: c.262C>A p.His88Asn |
| Inheritance | mosaic | inherited | de novo | de novo | mosaic | de novo | de novo |
| NGS; altered allele reads/total read depth | 0.28 (811/2,858)a | 0.55 (41/74) | detected via Sanger sequencing; equal representation of altered and reference alleles in sequencing chromatograms | 0.42 (102/239) | 0.32 (39/122) | 0.54 (20/37) | 0.31 (4/13) (the mutant allele was demonstrated to be in the heterozygous state in blood-derived DNA of P7 [~59% mutant allele frequency] and absent in both parents via droplet digital PCR [ddPCR]) |
| Other affected family members | yes, two offspring with postaxial polydactyly of both hands, short limbs, and congenital heart septal defects; both died early after birth; an IUFD at 33 weeks of gestation with bilateral postaxial polydactyly and congenital heart disease and a fetus with similar manifestations | yes, one affected fetus with short limbs, narrow thorax, postaxial polydactyly of both hands, and complete AVSD | no | no | no | no | no |
| Other information | surgery for a lobar emphysema in the left lung at the age of 2 years | the fetus presented with bicornuate and didelphys uterus; lungs with immature parenchyma at canalicular stage were also observed | dural ectasia and osteoporosis with multiple fractures |
P: Proband. M: median or 50th percentile. AVSD: atrioventricular septal defect. WAD: Weyers acrodental dysostosis. EvC: Ellis-van Creveld syndrome. IUFD: Intrauterine fetal death. NGS: next-generation sequencing.
a
To further confirm the mosaic state of the mutation detected by initial standard WES, additional deep WES was carried out in P1. Deep WES was also performed in the father of P2 (altered allele reads (508)/total read depth (3,097) = 0.16).