OMIA 002103-9913 : Developmental duplications in Bos taurus
Following development of a diagnostic PCR test for heterozygous and homozygous carriers, based on the above-mentioned discovery of a likely causal variant, Dr Laurence Denholm tested a consecutive series of Angus calves in Australia which presented with any visible anatomic malformation and demonstrated that the majority of Angus calves (but not all) with lesions that have previously been associated with neural tube defects (NTD) in other species were homozygous for the mutation identified in the polymelia cases.
Parnell et al. (2014) reported that the frequency of the variant when it was identified in 2013 was approx. 8% and 6% in the Australian and U.S. registered Angus populations respectively, with approx. 50% of the expected number of homozygotes present in these populations as apparently normal individuals. The incidence of malformed newborn calves could not explain the expected number of homozygotes missing from these populations and high early embryonic mortality was suspected. Subsequently, Delhotel et al. (2016) reported three separate mouse strains produced by the TALEN technique with 4, 12 and 19 base pair deletions in the NHLRC2 gene adjacent to the locus of the DD mutation in Angus cattle. There was 100% embryonic mortality in the mutant homozygotes of all 3 strains. Investigation of embryonic mortality in the 12 bp deletion strain indicated that embryonic death occurred after implantation but before embryonic day E8.5. More recently, polymelia and other lesions associated with neural tube defects have been reported in children from a small tribal group in Niger, some from consanguineous parents (Kelani et al., 2016).
(Text provided jointly by FN and Laurence Denholm)Inheritance: A GWAS conducted by Prof. Beever showed clear evidence of a recessive mutation in a single autosomal gene. However, the likely causal variant shows incomplete penetrance and variable expressivity: not all homozygotes for the likely causal variant show signs of polymelia (at least externally) or any other NTD-related lesion, and the extent and location of supernumerary limbs varies considerably. In effect, this evidence points to DD being a polygenic/multifactorial developmental disorder with one (known) gene of large effect contributing to the phenotypic variation. (Text provided jointly by FN and Laurence Denholm) Molecular basis: Starting with a GWAS on genetically related polymelia affected and normal Angus calves under an assumption of recessive inheritance, Prof. Beever identified a likely causal mutation for this disorder in August 2013. The mutation was disclosed by Beever et al. (2014): a "non-synonymous substitution was identified within exon 5 of the bovine NHL repeat containing 2 (NHLRC2) gene causing a valine to alanine substitution at residue 311 (V311A) of the encoded protein. Comparative analysis using the protein sequence from diverse taxa indicates the amino acid valine is invariable among the 53 species with sequence available.” (Text provided jointly by FN and Laurence Denholm) Clinical features: Many informative photographs of this disorder are provided by Dr Laurence Denholm at
Dr Denholm has also provided the following notes:
"The many different DD phenotypes are apparently the sequelae of an underlying neural tube defect (NTD).
The most common DD phenotype is occipital cranioschisis with meningocoele, with or without lipoma, myolipoma or teratoma. A few of these cases present as cephalomelia, but most do not. Meningocoele is also the most common phenotype in murine NTD syndromes and is common in human NTD.
Meningocoele and other lesions of cranial dysraphism are more common than polymelia in DD calves and also more common than lesions related to spinal dysraphism. This is consistent with our observation that, in DD calves with polymelia, supernumerary forelimbs are more common than supernumerary hindlimbs.
Nonetheless, by far the most common outcome for DD homozygotes is early embryonic death and resorption or undetected abortion, as demonstrated by the population genotype ratios in DD. High early embryonic mortality is also reported in murine NTD syndromes - both genetic and toxicological NTD syndromes.
Some DD homozygous calves have isolated lesions, but the majority have multiple lesions from the list described below. The occurrence of polymelia with other NTD associated lesions supports the idea that supernumerary limbs are dysraphic appendages.
The main phenotypes in homozygous DD calves are described below, with the more common at the top and less common at the bottom.
Cranioschisis (usually occipital) with meningocoele. The larger meningocoeles are usually associated with a lipoma, myolipoma or teratoma, often quite large and directly attached to the outside of the meninges lining the meningocoele. Dermoid cysts and/or dermoid sinuses are also common in the tissue surrounding these large meningocoeles. In some of the smaller menigocoeles with a small cranioschisis, there is stricture and subsequent fibrosis at the base of the meningocoele (within the cranioschisis) and subsequent resorption of the CSF trapped in the meningocoele. The resulting "rudimentary meningocoele" then looks like an elongated skin flap or pouch on the midline between the ears. Some DD calves have more than one of these rudimentary meningocoele skin flaps, each associated with its own small midline cranioschisis..
Exencephaly occurs when the meningeal membranes covering the brain tissue in a meningoencephalocoele are lost.
Cranial and vertebral clefts on the dorsal midline often accompany these cranial dysraphism related lesions.
Cerebral dysmorphogenesis, sometimes with anatomic duplication or neural hamartoma in the midbrain.
Diprosopus (partial duplication of the skull associated with duplication of the brain anterior to the diencephalon)
Microphthalmia (with or without cleft palate)
Polymelia (cephalomelia, notomelia, pygomelia)
Heteropagus conjoined twins (including rachipagus conjoined twins)
Spinal teratoma (embryogenic teratoma a.k.a. mature cell teratoma)
Spina bifida (with or without myelomeningocoele)
Split cord syndrome (diastematomyelia)
Caudal duplication syndrome (duplication of the caudal vertebrae, pelvis or parts of the pelvis, with additional hindlimbs)
Gastroschisis with intestinal eventration (seen with other lesions of DD in three cases)
We have also had a report of dicephalus in the progeny of two known DD carriers, but homozygosity of the affected calf was not confirmed by DNA testing for the NHLRC2 mutation. (Dicephalus is likely to occur in DD given that diprosopus is unusually common in DD.)
The phenotypes described above are well described in association with cranial dysraphism and/or spinal dysraphism in the medical and veterinary literature. For example, most of these lesions are reported in neonatal mice exposed to carefully timed retinoic acid toxicity during early embryonic development.
Importantly, this NHLRC2 mutation in Angus calves is the first mutation described at the molecular level in any species that is causally associated with a high incidence of conjoined twins.”Genetic testing: A DNA test for the causal allele is available from the Animal Genetics Laboratory in the School of Veterinary Science at the University of Queensland; from Neogen Corporation (GeneSeek), Lincoln, Nebraska; and from Zoetis Inc. (Text provided jointly by FN and Laurence Denholm) Breed: Angus. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|NHLRC2||NHL repeat containing 2||Bos taurus||26||NC_037353.1 (34307090..34362850)||NHLRC2||Homologene, Ensembl, NCBI gene|
By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.
WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
|Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Year Published||PubMed ID(s)||Acknowledgements|
|Angus||Developmental duplications||NHLRC2||missense||UMD3.1||26||g.34618072T>C||c.932T>C||p.V311A||2014||Reference not in PubMed; see OMIA 002103-9913 for reference details||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; Breed information kindly provided or confirmed by Matt McClure and Jennifer McClure from "Understanding Genetics and Complete Genetic Disease and Trait Definition (Expanded 2016 Edition)" (https://www.icbf.com/wp/?page_id=2170)|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2017||Kelani, A.B., Moumouni, H., Issa, A.W., Younsaa, H., Fokou, H., Sani, R., Sanoussi, S., Denholm, L.J., Beever, J.E., Catala, M. :|
|Notomelia and related neural tube defects in a baby born in Niger: case report and literature review. Childs Nerv Syst 33:529-534, 2017. Pubmed reference: 28083641. DOI: 10.1007/s00381-017-3337-x.|
|2016||Delhotel, J.D., Beever, J.E., Marron, B.H., Phillips, A.M. :|
|Characterization of a Mouse Model for Bovine Developmental Duplications Plant and Animal Genome Conference XXIV San Diego CA January :Abstract P0107, 2016.|
|2015||Denholm, L., Marron, B., Parnell, P., Teseling, C., Beever, J. :|
|Pleiotropic embryonic malformation associated with cranial and caudal neural tube defects from a single amino-acid substitution (V311A) at a conserved locus in the Nhlrc2 protein Proceedings of the 9th International Conference on Neural Tube Defects, University of Texas in Austin TX :, 2015.|
|2014||Beever, J.E., Marron, B.M., Parnell, P.F., Teseling, C.F., Steffen, D.J., Denholm, L.J. :|
|Developmental Duplications (DD): 1. Elucidation of the underlying molecular genetic basis of polymelia phenotypes in Angus cattle. Proc. XXVIII World Buiatrics Congress, Cairns Australia :Abstract 0106, 2014.|
|Denholm, L.J., Martin, L.E., Teseling, C.F., Parnell, P.F., Beever, J.E. :|
|Developmental Duplications (DD): 2. Mutation of the NHLRC2 gene causes neural tube defects in Angus cattle with multiple congenital malformation phenotypes that include axial and limb duplications, heteropagus conjoined twins, midbrain and forebrain malformations including pseudoholoprosencephalon, craniofacial dysmorphogenesis, micropthalmia, diprosopus, embryogenic teratomas, dermoid cysts, myolipomas, split cord malformation and cranial and spinal dysraphism. Proc. XXVIII World Buiatrics Congress, Cairns Australia :Abstract 0100, 2014.|
|Parnell, P.F., Teseling, C.F., Denholm, L.J., Beever, J.E. :|
|Developmental Duplications (DD): 3. Evidence of the frequency and impact of the causal mutation in the recorded Angus population and strategies adopted to reduce the carrier frequency using selective DNA based diagnostic testing, computation of associated genotype classes and publication of carrier probabilities to assist in future breeding decisions. Proc. XXVIII World Buiatrics Congress, Cairns Australia :Abstract 0101, 2014.|
|2013||Denholm, L.J., Martin, L.E. :|
|Developmental duplications in Angus calves Flock and Herd case notes; http://www.flockandherd.net.au/cattle/reader/developmental-duplication-angus.html :, 2013.|
|2011||Denholm, L.J., Martin, L.E. :|
|Polymelia (supernumerary limbs) in Angus calves Flock and Herd case notes; http://www.flockandherd.net.au/cattle/reader/polymelia.html :, 2011.|
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