Clinical investigations performed for each study participant
| Trio* | Diagnostic work-up |
|---|---|
| 1 | Karyotype, rapid aneuploidy detection, chromosomal microarray, pAA, uOA, lysosomal enzyme work-up, MPS testing, Noonan panel (13 genes), thrombophilia workup |
| 2 | Karyotype, chromosomal microarray, uAA |
| 3 | Acylcarnitine profile, pAA, uOA, pyruvate dehydrogenase and pyruvate carboxylase levels, respiratory chain enzymology (reduced activity of complex I and IV), lactate (19.8 mmol) |
| 4 | Sequencing of nuclear encoded mitochondrial gene panel, mitochondrial point mutation analysis, lactate carnitine, acylcarnitine, VLCFA, TIF, pAA, uOA, biotinidase, pyruvate dehydrogenase, pyruvate carboxylase, alpha amino adipic semialdehyde, MRI and metabolic workup suggestive of a mitochondrial disease |
| 5 | Chromosomal microarray, SLC2A1 sequencing, pAA, uOA, carnitine, acylcarnitine profile, VLCFA, MPS, TIF, neurotransmitter metabolites, MECP2 testing, cerebrospinal fluid (pyruvate, lactate, total protein, glucose, organic and amino acids) |
| 6 | Chromosomal microarray, cutis laxa autosomal recessive panel (6 genes), uOA, pAA, MPS and oligosaccharide screening |
| 7 | Chromosomal microarray, muscle biopsy, MRI, MYH8 testing |
| 8 | MTM1 sequencing, uOA, pAA |
| 9 | Karyotype, chromosomal microarray, Prader–Willi testing, MPS and oligosaccharide screening, TIF, serum β-hexosaminidase |
| 10 | Chromosomal microarray, Costello syndrome testing (HRAS), acylcarnitine profile, Noonan panel (13 genes) |
| 11 | Rapid aneuploidy detection, chromosomal microarray, uOA, acylcarnitine profile, MPS and oligosaccharidosis screening, VLCFA, TIF, 7DHC, galactosemia, sequencing and deletion/duplication analysis for IFT180 and DYNC2H1 |
| 12 | Karyotype, chromosomal microarray, 7DHC, CHD7 and FANCA squencing, Diamond Blackfan anemia panel, FISH for 22q11 deletion |
| 13 | Karyotype; chromosomal microarray; Noonan panel (13 genes); PTEN, PIK3CA and AKT1 testing |
| 14 | Chromosomal microarray, CHD7 testing |
| 15 | Karyotype, FISH for chromosome 18, X and Y, chromosomal microarray, DMPK expansion detection, uOA, CK, lactate, SMN1 and SMN2 deletion testing, MTM1 sequencing, EMG, NCS, muscle biopsy, oxidative phosphorylation testing, mitochondrial DNA testing, congenital myasthenic syndrome panel |
| 16 | Karyotype, chromosomal microarray, TIF, pAA, uOA, 7DHC, KMT2D testing, Angelman syndrome testing, TCF4 testing, EHMT1 testing |
| 17 | Chromosomal microarray, DMPK expansion testing, Prader–Willi testing, pAA, uOA, carnitine, acylcarnitine profile, VLCFA, muscle biopsy |
| 18 | Karyotype, chromosomal microarray |
| 19 | Karyotype, chromosomal microarray |
| 20 | Karyotype, chromosomal microarray, FISH for 22q11 deletion |
Note: CK = creatine kinase, EMG = electromyography, FISH = fluorescence in situ hybridization, MPS = mucopolysaccharide, MRI = magnetic resonance imaging, NCS = nerve conduction studies, pAA = plasma amino acids, TIF = transferrin isoelectric focusing, uAA = urinary amino acid, uOA = urinary organic acid, VLCFA = very long chain fatty acids, 7DHC = 7-dehydrocholesterol.
↵* Trio = newborn + parents.