Gene Discovery in Lethal Foetal Disorders


Prenatal ultrasonography identifies an increasing number of foetal malformation phenotypes of unknown cause. For a significant number of these often lethal phenotypes, the underlying causal mutations are not identified yet, but animal data predict that up to 30% of the protein‐coding genes of our genome are implicated in embryonic development. Little attention has been paid to gene identification in these disorders, which often may present with a specific but so far unrecognised phenotype during foetal life. Counselling in prenatal diagnosis clinics to inform prognosis and management decisions but also recurrence risk in these situations remains unsatisfactory. Next‐generation sequencing offers unprecedented opportunities and perspectives to unravel the Mendelian basis of foetal disorders.

Key Concepts

  • Malformations and genetic disorders are the leading cause of infant mortality in the developed countries accounting for more than one third of cases.
  • Foetal structural anomalies, often serious or lethal and of unknown cause despite current diagnostic genetic testing available, are increasingly identified at earlier gestational ages due to advancing ultrasound techniques.
  • Counselling to inform prognosis and management decisions but also recurrence risk in these situations remains unsatisfactory.
  • By identification of rare variants through whole exome or genome sequencing, many mutations in additional genes have been discovered to cause postnatal disease phenotypes.
  • Next‐generation sequencing technologies have rarely been used to discover genes in which mutations cause early embryonic and foetal maldevelopment.
  • On the basis of analysis of knockout and spontaneous mouse models, loss‐of‐function variants in up to 30% of genes could result in embryonic lethality in humans.
  • Studying genes implicated in embryonic and foetal development and their phenotypes reveals important biological information on early errors in human morphogenesis and will contribute to annotate the function of relevant protein‐coding genes in our genome.
  • Reliable applications of NGS strategies in future prenatal diagnosis will depend on our knowledge on specific foetal genotype–phenotype correlations.

Keywords: foetal; exome; exome sequencing; prenatal; lethal; lethal foetal; recessive lethal; loss of function; Mendelian; ultrasound

Figure 1. A strikingly large proportion of about one third of targeted knockouts and recessive spontaneous mutations in mice result in embryonic or perinatal death. Mutations in up to 30% of our human protein‐coding genes are predicted to cause embryonic lethality in humans. Adapted from Chong et al. © Elsevier.
Figure 2. Challenges and perspectives in gene discovery for foetal malformation phenotypes.


Alamillo CL, Powis Z, Farwell K, et al. (2015) Exome sequencing positively identified relevant alterations in more than a half of cases with an indication of prenatal ultrasound anomalies. Prenatal Diagnosis 35: 1–6.

Alazami AM, Awad SM, Coksun S, et al. (2015) TLE6 mutation causes the earliest known human embryonic lethality. Genome Biology 16: 240–248.

Alkuraya FS (2015) Human knockout research. New horizons and opportunities. Trends in Genetics 31 (2): 108–115.

American College of Obstetricians and Gynecologists Committee on Genetics (2013) Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstetrics and Gynecology 122 (6): 1374–1377.

Baird PA, Anderson TW, Newcombe HB, et al. (1988) Genetic disorders in children and young adults: a population study. American Journal of Human Genetics 42: 677–693.

Bellini C, Donarini G, Paladini D, et al. (2015) Etiology of non‐immune hydrops fetalis: an update. American Journal of Medical Genetics, Part A 167A: 1082–1088.

Bittles AH and Neel JV (1994) The costs of human inbreeding and their implications for variations at the DNA level. Nature Genetics 8: 117.

Carss KJ, Hillman SC, Parthiban V, et al. (2014) Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Human Molecular Genetics 23 (12): 3269–3277.

Casey JP, Brennan K, Scheidel N, et al. (2016) Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle and ciliary defects. Human Molecular Genetics 25 (9): 1824–1835.

Chiu RW and Lo YM (2013) Clinical applications of maternal plasma fetal DNA analysis: translating the fruits of 15 years of research. Clinical Chemistry and Laboratory Medicine 51 (1): 197–204.

Chong JX, Buckingham KJ, Jhangiani SN, et al. (2015) The genetic basis of Mendelian phenotypes: discoveries, challenges and opportunities. American Journal of Human Genetics 98: 199–215.

Drury S, Williams H, Trump N, et al. (2015) Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenatal Diagnosis 35: 1–8.

Filges I and Friedman JM (2014) Exome sequencing for gene discovery in lethal fetal disorders – harnessing the value of extreme phenotypes. Prenatal Diagnosis 35: 1005–1009.

Filges I, Nosova E, Bruder E, et al. (2014) Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype. Clinical Genetics 86 (3): 220–228.

Filges I, Bruder E, Brandal K, et al. (2016) Strømme syndrome is a ciliary disorder caused by mutations in CENPF. Human Mutation 37 (4): 359–363.

Fujikura K, Setsu T, Tanigaki K, et al. (2013) Kif14 mutation causes severe brain malformation and hypomyelination. PLoS One 8 (1): e53490.

Gaj T, Gersbach CA and Barbas CF III (2013) ZFN, TALEN and CRISPR/Cas‐based methods for genome engineering. Trends in Biotechnology 31: 397–405.

Gilissen C, Hoischen A, Brunner HG and Veltman JA (2012) Disease gene identification strategies for exome sequencing. European Journal of Human Genetics 20 (5): 490–497.

Hillman SC, McMullan DJ, Hall G, et al. (2013) Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta‐analysis. Ultrasound in Obstetrics and Gynecology 41 (6): 610–620.

Kariminejad A, Ghaderi‐Sohi S, Hossein‐Nejad Nedai H, et al. (2016) Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum. BMC Musculoskeletal Disorders 17: 109–114.

Lalonde E, Albrecht S, Ha KC, et al. (2010) Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next‐generation exome sequencing. Human Mutation 31 (8): 918–923.

de Ligt J, Boone PM, Pfundt R, et al (2013) Detection of clinically relevant copy number variants with whole‐exome sequencing. Human Mutation 34 (10): 1439–1448.

Linda AS, Bupp CP, McGee SJ, et al. (2014) Truncating mutations in lRP4 lead to a prenatal lethal form of Cenani–Lenz syndrome. American Journal of Medical Genetics, Part A 164A: 2391–2397.

Lo YM, Chan KC, Sun H, et al. (2010) Maternal plasma DNA sequencing reveals the genome‐wide genetic and mutational profile of the fetus. Science Translational Medicine 2 (61): 61ra91.

MacArthur DG, Balasubramanian S, Frankish A, et al. (2012) A systematic survey of loss‐of‐function variants in human protein‐coding genes. Science 335: 823–828.

Markus B, Narkis G, Landau D, et al. (2012) Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a mutation in MYBPC1. Human Mutation 33 (10): 1435–1438.

McCune AR, Fuller RC, Aquilina AA, et al. (2002) A low genomic number of recessive lethals in natural populations of bluefin killifish and zebrafish. Science 296: 2398.

McInerney‐Leo AM, Schmidts M, Cortes CR, et al. (2013) Short‐rib polydactyly and Jeune syndromes are caused by mutations in WDR60. American Journal of Human Genetics 93 (3): 515–523.

Michalk A, Stricker S, Becker J, et al. (2008) Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. American Journal of Human Genetics 82 (2): 464–476.

Mohun T, Adams DJ, Baldock R, et al. (2013) Deciphering the mechanisms of developmental disorders (DMDD): a new programme for phenotyping embryonic lethal mice. Disease Models & Mechanisms 6 (3): 562–566.

Putoux A, Thomas S, Coene KL, et al. (2011) KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nature Genetics 43 (6): 601–606.

Ramos E, Bien‐Willner G, Li J, et al. (2013) Genetic variation in MKL2 and decreased downstream PCTAIRE1 expression in extreme, fatal primary human microcephaly. Clinical Genetics 85 (5): 423–432.

Ravenscroft G, Thompson EM, Todd EJ, et al. (2013) Whole exome sequencing in foetal akinesia expands the genotype‐phenotype spectrum of GBE1 glycogen storage disease mutations. Neuromuscular Disorders 23 (2): 165–169.

Robinson PN, Kohler S, Oellrich A, et al (2014) Improved exome prioritization of disease genes through cross‐species phenotype comparison. Genome Research 24 (2): 340–348.

Rossi AC and Prefumo F (2013) Accuracy of ultrasonography at 11‐14 weeks of gestation for detection of fetal structural anomalies: a systematic review. Obstetrics and Gynecology 122 (6): 1160–1167.

Shamseldin HE, Swaid A and Alkuraya FS (2013) Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing. Genetics in Medicine 15 (4): 307–309.

Strømme P, Dahl E, Flage T, et al. (1993) Apple peel intestinal atresia in siblings with ocular anomalies and microcephaly. Clinical Genetics 52: 133.

Talkowski ME, Ordulu Z, Pillalamarri V, et al. (2012) Clinical diagnosis by whole‐genome sequencing of a prenatal sample. New England Journal of Medicine 367 (23): 2226–2232.

Thomas S, Legendre M, Saunier S, et al. (2012) TCTN3 mutations cause Mohr‐Majewski syndrome. American Journal of Human Genetics 91 (2): 372–378.

Tsurusaki Y, Kosho T, Hatasaki K, et al. (2013) Exome sequencing in a family with an X‐linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients. Clinical Genetics 83 (2): 135–144.

Valence S, Poirier K, Lebrun N, et al. (2013) Homozygous truncating mutation of the KBP gene, encoding a KIF1B‐binding protein, in a familial case of fetal polymicrogyria. Neurogenetics 14 (3‐4): 215–224.

Veltman JA and Brunner HG (2012) De novo mutations in human genetic disease. Nature Reviews Genetics 13 (8): 565–575.

Vissers LE, de Ligt J, Gilissen C, et al. (2010) A de novo paradigm for mental retardation. Nature Genetics 42 (12): 1109–1112.

Waters AM, Asfashani R, Carroll P, et al. (2015) The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes. Journal of Medical Genetics 3: 147–156.

Watson CM, Crinnion LA, Murphy H, et al. (2016) Deficiency of the myogenic factor MyoD causes a perinatally lethal fetal akinesia. Journal of Medical Genetics 53: 264–269.

Webber DM, MacLeod SL, Bamshad MJ, et al. (2015) Developments in our understanding of the genetic basis of birth defects. Birth Defects Research Part A 103: 680–691.

Xue L, Cai JY, Ma J, et al. (2013) Global expression profiling reveals genetic programs underlying the developmental divergence between mouse and human embryogenesis. BMC Genomics 14: 568.

Yang Y, Muzny DM, Reid JG, et al. (2013) Clinical whole‐exome sequencing for the diagnosis of Mendelian disorders. New England Journal of Medicine 369 (16): 1502–1511.

Further Reading

Adams D, Baldock R, Bhattacharya S, et al. (2013) Bloomsbury report on mouse embryo phenotyping: recommendations from the IMPC workshop on embryonic lethal screening. Disease Models and Mechanisms 6 (3): 571–579.

Blaas HG (2014) Detection of structural abnormalities in the first trimester using ultrasound. Best Practice & Research. Clinical Obstetrics & Gynaecology 28 (3): 341–353.

Chitty LS, Friedman JM and Langlois S (2015) Current controversies in prenatal diagnosis 2: should a fetal exome be used in the assessment of a dysmorphic or malformed fetus? Prenatal Diagnosis 35: 1–5.

Kohler S, Doelken SC, Ruef BJ, et al. (2013) Construction and accessibility of a cross‐species phenotype ontology along with gene annotations for biomedical research. Version 2. F1000Res. 2: 30.

Wapner RJ, Martin CL, Levy B, et al. (2012) Chromosomal microarray versus karyotyping for prenatal diagnosis. New England Journal of Medicine 367 (23): 2175–2184.

Xue L, Yi H, Huang Z, et al. (2011) Global gene expression during the human organogenesis: from transcription profiles to function predictions. International Journal of Biological Science 7 (7): 1068–1076.

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Filges, Isabel(Jan 2017) Gene Discovery in Lethal Foetal Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026660]