Death in the fetal, perinatal, and early infant age-group has a multitude of causes, a proportion of which is presumed to be genetic. Defining a specific genetic aberration leading to the death is problematic at this young age, due to limited phenotype–genotype correlation inherent in the underdeveloped phenotype, the inability to assess certain phenotypic traits after death, and the problems of dealing with rare disorders. In this study, our aim was to increase the yield of identification of a defined genetic cause of an early death. Therefore, we employed whole genome sequencing and bioinformatic filtering techniques as a comprehensive, unbiased genetic investigation into 16 fetal, perinatal, and early infant deaths, which had undergone a full autopsy. A likely genetic cause was identified in two cases (in genes; COL2A1 and RYR1) and a speculative genetic cause in a further six cases (in genes: ARHGAP35, BBS7, CASZ1, CRIM1, DHCR7, HADHB, HAPLN3, HSPG2, MYO18B, and SRGAP2). This investigation indicates that whole genome sequencing is a significantly enabling technology when determining genetic causes of early death.
DrmanacRSparksABCallowMJet al.Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science2010; 327: 78–81.
2.
HiltemannSMeiHde HollanderMet al.CGtag: complete genomics toolkit and annotation in a cloud-based Galaxy. Gigascience2014; 3: 1.
3.
LekMKarczewskiKJMinikelEVet al.Analysis of protein-coding genetic variation in 60,706 humans. Nature2016; 536: 285–291.
4.
BirneyESoranzoN. Human genomics: the end of the start for population sequencing. Nature2015; 526: 52–53.
5.
EriksonGABodianDLRuedaMet al.Whole-genome sequencing of a healthy aging cohort. Cell2016; 165: 1002–1011.
6.
RichardsSAzizNBaleSet al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med2015; 17: 405–424.
7.
WilkinDJArtzASSouthSet al.Small deletions in the type II collagen triple helix produce Kniest dysplasia. Am J Med Genet1999; 85: 105–112.
8.
Cirillo SilengoMDaviGFBiancoRDeMarcoAFranceschiniP. Kniest disease with Pierre Robin syndrome and hydrocephalus. Pediatr Radiol1983; 13: 106–109.
BasiriKFatehiFKatirjiB. The Schwartz-Jampel syndrome: case report and review of literature. Adv Biomed Res2015; 4: 163.
11.
StumMDavoineCSVicartSet al.Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome. Hum Mutat2006; 27: 1082–1091.
12.
RodgersKDSasakiTAszodiAJacenkoO. Reduced perlecan in mice results in chondrodysplasia resembling Schwartz-Jampel syndrome. Hum Mol Genet2007; 16: 515–528.
13.
MalfattiEBohmJLaceneEBeuvinMRomeroNBLaporteJ. A premature stop codon in MYO18B is associated with severe nemaline myopathy with cardiomyopathy. J Neuromuscul Dis2015; 2: 219–227.
14.
GurungROnoYBaxendaleSet al.A zebrafish model for a human myopathy associated with mutation of the unconventional myosin MYO18B. Genetics2017; 205: 725–735.
15.
AklKFKhudrGSDer KaloustianVMNajjarSS. The Smith-Lemli-Opitz syndrome. Report of a consanguineous Arab infant with bilateral focal renal dysplasia. Clin Pediatr (Phila)1977; 16: 665–668.
16.
KalbSCaglayanAODegerliyurtAet al.High frequency of p.Thr93Met in Smith-Lemli-Opitz syndrome patients in Turkey. Clin Genet2012; 81: 598–601.
17.
Witsch-BaumgartnerMClaytonPClusellasNet al.Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy. Hum Mutat2005; 25: 412.
18.
SaisawatPTasicVVega-WarnerVet al.Identification of two novel CAKUT-causing genes by massively parallel exon resequencing of candidate genes in patients with unilateral renal agenesis. Kidney Int2012; 81: 196–200.
19.
TerroneGRuoppoloMBrunetti-PierriNet al.Child neurology: recurrent rhabdomyolysis due to a fatty acid oxidation disorder. Neurology2014; 82: e1–4.
20.
SojkaSAminNMGibbsDChristineKSCharpentierMSConlonFL. Congenital heart disease protein 5 associates with CASZ1 to maintain myocardial tissue integrity. Development2014; 141: 3040–3049.
BealesPLBadanoJLRossAJet al.Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet2003; 72: 1187–1199.
23.
DeveaultCBillingsleyGDuncanJLet al.BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition. Hum Mutat2011; 32: 610–619.
24.
FishJEWytheJDXiaoTet al.A Slit/miR-218/Robo regulatory loop is required during heart tube formation in zebrafish. Development2011; 138: 1409–1419.
25.
CharrierCJoshiKCoutinho-BuddJet al.Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell2012; 149: 923–935.
CastilloAKramerNSchwartzCEet al.19q13.32 Microdeletion syndrome: three new cases. Eur J Med Genet2014; 57: 654–658.
28.
ChiuHSYorkJPWilkinsonLZhangPLittleMHPennisiDJ. Production of a mouse line with a conditional Crim1 mutant allele. Genesis2012; 50: 711–716.
29.
PennisiDJKinnaGChiuHSSimmonsDGWilkinsonLLittleMH. Crim1 has an essential role in glycogen trophoblast cell and sinusoidal-trophoblast giant cell development in the placenta. Placenta2012; 33: 175–182.
30.
IyerSPennisiDJPiperM. Crim1-, a regulator of developmental organogenesis. Histol Histopathol2016; 31: 1049–1057.
31.
BeleggiaFLiYFanJet al.CRIM1 haploinsufficiency causes defects in eye development in human and mouse. Hum Mol Genet2015; 24: 2267–2273.
32.
SpicerAPJooABowlingRAJr. A hyaluronan binding link protein gene family whose members are physically linked adjacent to chondroitin sulfate proteoglycan core protein genes: the missing links. J Biol Chem2003; 278: 21083–21091.
33.
LockhartMWirrigEPhelpsAWesselsA. Extracellular matrix and heart development. Birth Defects Res A Clin Mol Teratol2011; 91: 535–550.
34.
ItoYSenoSNakamuraHFukuiAAsashimaM. XHAPLN3 plays a key role in cardiogenesis by maintaining the hyaluronan matrix around heart anlage. Dev Biol2008; 319: 34–45.
35.
OgawaHOohashiTSataMet al.Lp3/Hapln3, a novel link protein that co-localizes with versican and is coordinately up-regulated by platelet-derived growth factor in arterial smooth muscle cells. Matrix Biol2004; 23: 287–298.
36.
Van AllenMICurryCGallagherL. Limb body wall complex: I. Pathogenesis. Am J Med Genet1987; 28: 529–548.
WilligLKPetrikinJESmithLDet al.Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med2015; 3: 377–387.
39.
DaoudHLucoSMLiRet al.Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit. Cmaj2016; 188: E254–260.
40.
NeubauerJLeccaMRRussoGet al.Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases. Eur J Hum Genet2017; 25: 404–409.
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