Article Figures & Tables
Tables
Trio* Enrolment Clinical description Family history Gestional age at birth, wk+d Time in hospital, d Turnaround time,† wk 1 Prospective Hydrops, bilateral pleural effusion – 35 99 20 2 Prospective Oligohydramnios, vasopressin-dependent hypotension, anuric acute renal failure; at discharge, mild chronic kidney disease – 27+4 119 58 3 Prospective Transient neonatal hyperlactatemia Father affected 40+3 7 3 4 Prospective Epileptic encephalopathy (Ohtahara syndrome), renal failure, anemia; died at 59 days of life – 37+2 59 2 5 Prospective Generalized hypotonia, horseshoe kidney, recurrent apnea, nystagmus, seizures; later assessment: developmental delay – 34+1 113 32 6 Prospective Bilateral inguinal hernias, flexion contractures of limbs, bilateral hip dysplasia, bilateral foot clubbing; early-onset multifocal seizures – 40+5 6 20 7 Retrospective Congenital trismus, feeding difficulties (gastrostomy tube feeding required), limited facial expression, reduced rate of blinking, limited eye movements – 39 78 26 8 Prospective Hypotonia with respiratory distress requiring intubation; died at 33 days of life Maternal uncle affected 33+2 33 2 9 Retrospective Feeding difficulties and severe influx (gastrostomy tube feeding required), vision impairment, left ventricular cardiomyopathy; distinctive facial features with synophrys; later assessment: global developmental delay Consanguineous parents 38+3 34 18 10 Retrospective Cleft palate, VSD, laryngomalacia, ptosis, conductive hearing loss, hypotonia, joint hypermobility, bilateral hip dysplasia, pancreatic cysts, hypoplastic corpus callosum; later assessment: global developmental delay, short stature, scoliosis – 37+4 26 8 11 Retrospective Hydrops, bilateral hernias, bilateral hip dysplasia, short limbs, brachydactyly, renal cysts, stenosis of foramen magnum, horseshoe kidney – 28 32 6 12 Retrospective Choanal atresia, bilateral preaxial polydactyly, multicystic kidneys, duplex left renal collecting system, bicuspid aortic valve, anemia, tracheomalacia, profound sensorineural hearing loss (cochlear implants required), axial hypotonia; later assessment: developmental delay and short stature – 37+4 22 7 13 Retrospective Macrosomia (head circumference +4 SD at birth, +6 to +7 SD at 18 mo), hydrocephalus requiring shunting, Chiari I malformation, hypoglycemia (transient), bicuspid aortic valve – 31 4 24 14 Retrospective Cleft lip and palate, DORV with severe subpulmonary stenosis and hypoplastic pulmonary valve, right renal agenesis – 39+2 41 22 15 Retrospective Ptosis, external ophthalmoplegia with right-sided amblyopia and strabismus, feeding difficulties, distal contractures, hypotonia, mild scoliosis, bilateral cryptorchidism, hyporeflexia Consanguineous parents 37+5 53 5 16 Retrospective Hypotonia; later assessment: global developmental delay, averbal, short stature, seizures – 37+2 12 9 17 Retrospective Hypotonia, congenital diaphragmatic hernia, feeding issues, flexion contracture of right third to fifth digits, torticollis; later assessment: developmental delay – 38+1 75 15 18 Retrospective IUGR, microcephaly, bilateral flexion contractures of PIP and DIP of third fingers, bilateral ankle contractures, hypertonicity, enlarged cisterna magna, dysmorphic facies; later assessment: global developmental delay Consanguineous parents 36+3 23 3 19 Prospective Congenital diaphragmatic hernia, nephrotic syndrome, nondysmorphic – 38+2 Still in hospital 17 20 Retrospective Tetralogy of Fallot, hypotonia; later assessment: global developmental delay, pica – 40+1 6 8 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.
Trio* Sex Affected gene Inheritance Mutation type NCBI RefSeq cDNA and protein changes identified Molecular diagnosis (OMIM no.) 2 M ACE Compound heterozygous Frameshift deletion NM_000789.3 c.819_820delAG; p.(Arg274Glyfs*117) Renal tubular dysgenesis (106180) Frameshift deletion NM_000789.3 c.3521delG; p.(Gly1174Alafs*12) 6 M SCN1A De novo Missense NM_001202435.1 c.620T>G; p.(Val207Gly) SCN1A-related encephalopathy syndrome (607208) 8 M MTM1 X-linked Nonsense NM_000252.2 c.584C>A; p.(Tyr198*) Myotubular myopathy, X-linked (310400) 9 F FTO Autosomal recessive Missense NM_001080432.2 c.956C>T; p.(Ser319Phe) FTO deficiency syndrome (612938) 11 M WDR19 Compound heterozygous Nonsense NM_025132.3 c.1600G>T; p.(Glu534*) Cranioectodermal dysplasia (614376) Missense NM_025132.3 c.2129T>C; p.(Leu710Ser) 15 M CHRND Autosomal recessive Splice site NM_000751.2 c.932+5G>A; p.? Congenital myasthenic syndrome (601462) 18 M DYRK1A De novo Splice site NM_001396.3 c.951+4_951+7delAGTA; p.? Autosomal dominant intellectual disability syndrome type 7 (614104) 19 F WT1 De novo Missense NM_024426.4 c.1460A>C; p.(His469Pro) Denys–Drash syndrome (194080) Note: cDNA = complementary DNA, NCBI = National Center for Biotechnology Information (US), OMIM = Online Mendelian Inheritance in Man.
↵* Trio = newborn + parents.