Table 1.
Overview of the patients’ genetic diagnosis and their respective contributions to the phenotypes.
| Case | Sex | Age at Diagnosis | Parental Consanguinity | 1st Diagnosis | 1st Molecular Mechanism | Features Caused by 1st Diagnosis | 2nd Diagnosis | 2nd Molecular Mechanism | Features Caused by 2nd Diagnosis | Phenotypic Overlap | Additional Features |
|---|---|---|---|---|---|---|---|---|---|---|---|
| CASE 1 | M | 20 years 1 month | Not known, probably “territorial” |
Multiple epiphyseal dysplasia, type 4 OMIM #226900 AR |
SLC26A2 hmz p.Arg279Trp, mat/pat |
Cleft palate, bilateral osteonecrosis of femoral head, short limbs | Bardet-Biedl syndrome 19 OMIM #615996 AR |
IFT27 hmz p.Gly117Asp, mat/pat |
Relative macrocephaly, cerebellar hypoplasia, kidney disease, post-axial polydactyly, anal stenosis | Brachyclynodactyly, bilateral clubfeet | Shawl scrotum |
| CASE 2 | F | 15 years 6 months | Yes (second cousins) | Ciliary dyskinesia, primary, 1, with or without situs inversus OMIM #244400 AR |
DNAI1 hmz p.Gly651Glu, mat/pat |
Complete situs viscerum inversus | Cholestasis, progressive familial intrahepatic 4 OMIM #615878 AR |
TJP2 hmz p.Gly532Arg, mat/pat |
Progressive cholestasis, liver cirrhosis, poor growth | / | Pubertal delay |
| CASE 3 | F | 2 years 8 months | Not reported | Ciliary dyskinesia, primary, 1, with or without situs inversus OMIM #244400 AR |
DNAI1 hmz p.Gly651Glu, mat/pat |
Complete situs viscerum inversus and polysplenia | Cholestasis, progressive familial intrahepatic 4 OMIM #615878 AR |
TJP2 hmz p.Gly532Arg, mat/pat |
Persistent pruritus, hepatosplenomegaly, increased serum bile acids, hypertransaminasemia | / | Mild psychomotor delay and minor facial anomalies |
| CASE 4 | F | 7 months | Yes (first cousins) | Severe combined immunodeficiency, Athabascan type OMIM #602450 AR |
DCLRE1C hmz p.Ser32Cys, mat/pat |
Failure to thrive, decreased numbers of B cells, agammaglobulinemia | Ataxia-teleangectasia OMIM #208900 AR |
ATM hmz p.Met2158fs, mat/pat |
Cafè-au-lait spots, hypo-/hyperpigmented macules | Immunodeficiency | / |
| CASE 5 | F | 14 years 4 months | No | Intellectual developmental disorder, with or without seizures OMIM #613970 #616139 AD |
GRIN2B htz p.Phe416Leu, de novo |
Dyskinetic movement disorder, autistic features and feeding difficulties | Developmental and epileptic encephalopathy OMIM #612949 AR |
SLC25A12 htz p.Arg586Gln, pat htz p.Phe39fs, de novo |
Lack of brain myelination, decreased N-acetyl aspartate on MR spectroscopy | Intellectual disability, epilepsy, hypotonia | Aspecific minor facial anomalies |
| CASE 6 | M | 4 years 9 months | Yes (first cousins) | Deafness, autosomal recessive 22 OMIM #607039 AR |
OTOA htz p.Arg202Gln, pat htz p.Thr322Ile, mat |
Sensorineural severe deafness | Ichthyosis OMIM #308100 X-linked recessive |
STS Xp22.31 deletion, mat |
Ichthyosis | / | / |
| CASE 7 | F | Right after birth (1st) and 5 years 9 months (2nd) | No | Prader-Willi syndrome OMIM #176270 Imprinting disorder |
Maternal UPD of 15q11.2-23 region * | Severe hypotonia, feeding difficulties, global developmental delay | Ceroid lipofuscinosis, neuronal, type 6A OMIM #601708 AR |
CLN6 hmz p.Tyr142fs, mat |
Progressive cognitive decline, loss of motor and language skills, cerebral and cerebellar atrophy, hypomyelination, EEG anomalies | / | / |
| CASE 8 | M | 2 months (1st) and 16 years old (2nd) | No | Williams-Beuren syndrome OMIM #194050 Genomic disorder |
7q11.23 microdeletion, de novo * | Perimembranous VSD, supravalvular aortic stenosis, distinctive facies, hypothyroidism, scoliosis | Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies OMIM #619556 AD |
TNPO2 htz p.Arg105ter, de novo |
Epilepsy, EEG abnormalities, developmental regression, important speech impairment, MRI brain abnormalities |
Intellectual disability, feeding difficulties, poor overall growth, myopia | Hypoplasia of the olfactory tracts |
|
Cianci et al., 2019
[5] |
F | 2 years and 6 months (1st) and 4 years and 7 months (2nd) | No | Neurofibromatosis, type 1 OMIM #162200 AD |
NF1 htz p.Lys2401fs, mat * |
Café-au-lait spots, groin and axillary freckling, UBOs at brain MRI | KBG syndrome OMIM #148050 AD |
ANKRD11 htz p.Phe904fs, de novo |
Postnatal short stature, moderate intellectual disability, facial dysmorphisms, macrodontia of upper central incisors | / | / |
|
Pezzani et al., 2019
[7] |
M | 4 months | Yes (first cousins) | Mosaic variegated aneuploidy syndrome 2 OMIM #614114 AR |
CEP57 hmz p.Leu309Profs*9, mat/pat |
IUGR, congenital hypothyroidism, congenital heart defects | Short-rib thoracic dysplasia 3 with or without polydactyly OMIM #613091 AR |
DYNC2H1 hmz p.Met3762Val, mat/pat |
Polydactyly, brachydactyly, cystic liver, recurrent respiratory infections | Rhizomelic shortening of the limbs and bell-shaped thorax | Butterfly vertebra, supernumerary rib, recurrent infections and immunodeficiency, vascular malformations |
* Not-detected by trio-WES. AD: autosomal dominant; AR: autosomal recessive; EEG: electroencephalogram; hmz: homozygous; htz: heterozygous; IUGR: intrauterine growth restriction; mat: maternal; MR: magnetic resonance; MRI: magnetic resonance imaging; pat: paternal; UBO: udinditified bright object; UPD: uniparental disomy; VSD: ventricular septal defect.