Recent advances in understanding inheritance of holoprosencephaly

Dubourg, Christèle; Kim, Artem; Watrin, Erwan; Tayrac, Marie de; Odent, Sylvie; David, Véronique; Dupé, Valérie

doi:10.1002/ajmg.c.31619

Cited by 49 publications

(59 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…13,14 HPE also occurs in a non-syndromic form with various modes of inheritance reported, including autosomal dominant with reduced penetrance and variable expressivity, autosomal recessive and a growing evidence of oligogenic inheritance. 4,15 The two patients reported in this study were diagnosed with alobar HPE in utero by ultrasound examination. Alobar HPE, which is the most severe subtype in the HPE spectrum, is classically characterized by agenesis of the corpus callosum and olfactory bulbs, fused thalami, a midline monoventricle and complete absence of the interhemispheric fissure with or without associated craniofacial defects.…”

Section: Discussionmentioning

confidence: 88%

“…Classically, HPE can occur in a non‐syndromic form or as part of recognizable monogenic conditions and chromosomal anomalies. To date, non‐syndromic HPE has been associated with pathogenic variants in nearly 17 genes, while syndromic HPE features in at least 25 monogenic conditions . The gene KMT2D has not been shown to play a major role in the regulation of human forebrain development.…”

Section: Introductionmentioning

confidence: 99%

“…To date, nonsyndromic HPE has been associated with pathogenic variants in nearly 17 genes, while syndromic HPE features in at least 25 monogenic conditions. 3,4 The gene KMT2D has not been shown to play a major role in the regulation of human forebrain development. KMT2D encodes a histone methyltransferase responsible for the trimethylation of the fourth lysine residue of histone H3 protein, which is an epigenetic mark associated with transcriptionally active genes.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel heterozygous variants in KMT2D associated with holoprosencephaly

et al. 2019

View full text Add to dashboard Cite

Lysine methyltransferase 2D (KMT2D; OMIM 602113) encodes a histone methyltransferase involved in transcriptional regulation of the beta‐globin and estrogen receptor as part of a large protein complex known as activating signal cointegrator‐2‐containing complex (ASCOM). Heterozygous germline mutations in the KMT2D gene are known to cause Kabuki syndrome (OMIM 147920), a developmental multisystem disorder. Neither holoprosencephaly nor other defects in human forebrain development have been previously associated with Kabuki syndrome. Here we report two patients diagnosed with alobar holoprosencephaly in their antenatal period with de novo monoallelic KMT2D variants identified by trio‐based exome sequencing. The first patient was found to have a stop‐gain variant c.12565G>T (p.Gly4189*), while the second patient had a missense variant c.5A>G (p.Asp2Gly). Phenotyping of each patient did not reveal any age‐related feature of Kabuki syndrome. These two cases represent the first report on association between KMT2D and holoprosencephaly.

show abstract

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel heterozygous variants in KMT2D associated with holoprosencephaly

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The previous study indicated this feline heritable brain malformation syndrome resembled a mild form of HPE [20]. Many genes have been reported to cause HPE in humans (Reviewed in [47][48][49]). However, GDF7, also known as bone morphology protein 12 (BMP12), has not been reported to be associated with HPE in humans.…”

Section: A Variant Dataset From Wgs Of Domestic Cats the 99 Lives Camentioning

confidence: 88%

“…In humans, heterogeneity in familial HPE is also identified even if different individuals are carrying the same mutation [51][52][53]. The influence of environmental or teratogenic factors or modifier genes have been suggested for the spectrum (Reviewed in [46,47,49]). Assuming no exposure to teratogen and relatively homogeneous living environment, the presence of modifier genes is suspected for the variable severity of the dilated ventricles and supratentorial cysts in cats presented here.…”

Section: A Variant Dataset From Wgs Of Domestic Cats the 99 Lives Camentioning

confidence: 99%

A deletion inGDF7is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats

Creighton

Buckley

et al. 2020

Preprint

View full text Add to dashboard Cite

An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test, a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing, and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99Lives dataset. The variant segregated concordantly in an extended pedigree. Obligate carrier cats were heterozygous. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasizes the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.

show abstract

Holoprosencephaly, orofacial cleft, and frontonaso‐orbital encephaloceles: Genetic evaluation of a possible new syndrome

Richieri-Costa

Zechi-Ceide

Candido-Souza

et al. 2019

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Here we report on a Brazilian child who presented semilobar holoprosencephaly, frontonasal encephaloceles and bilateral cleft lip and palate. Malformations also included agenesis of the corpus callosum, abnormal cortical gyres, dilation of the aqueduct, bilateral endolymphatic sac, bilateral cystic cocci-vestibular malformation, and a cribriform defect. The 3D TC craniofacial images showed abnormal frontonasal transition region, with a bone bifurcation, and partial agenesis of nasal bone. The trunk and upper and lower limbs were normal. To our knowledge, this rare association of holoprocensephaly with frontonaso-orbital encephaloceles without limb anomalies has never been reported before. Karyotype was normal. SNP-array showed no copy-number alterations but revealed 25% of regions of homozygosity (ROH) with normal copy number, indicating a high coefficient of inbreeding, which significantly increases the risk for an autosomal recessive disorder. Whole exome sequencing analysis did not reveal any pathogenic or likely pathogenic variants. We discuss the possible influence of two variants of uncertain significance found within the patient's ROHs. First, a missense p.(Gly394Ser) in PCSK9, a gene involved in the regulation of plasma low-density lipoprotein cholesterol. Second, an inframe duplication p.(Ala75_Ala81dup) in SP8, a zinc-finger transcription factor that regulates signaling centers during craniofacial development. Further studies and/or the identification of other patients with a similar phenotype will help elucidate the genetic etiology of this complex case. K E Y W O R D S encephalocele, holoprosencephaly, oral cleft, regions of homozygosity, SNP-array, SP8

show abstract

Recent advances in understanding inheritance of holoprosencephaly

Cited by 49 publications

References 77 publications

Novel heterozygous variants in KMT2D associated with holoprosencephaly

Novel heterozygous variants in KMT2D associated with holoprosencephaly

A deletion inGDF7is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats

Holoprosencephaly, orofacial cleft, and frontonaso‐orbital encephaloceles: Genetic evaluation of a possible new syndrome

Contact Info

Product

Resources

About