Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects

Beecroft, Sarah J.; Ayala, Marcos; McGillivray, George; Nanda, Vikas; Agolini, Emanuele; Novelli, Antonio; Digilio, María Cristina; Dotta, Andrea; Carrozzo, Rosalba; Clayton, Joshua S.; Gaffney, Lydia; McLean, Catriona; Ng, Jessica M.Y.; Laing, Nigel G.; Matteson, Paul G.; Millonig, James H.; Ravenscroft, Gianina

doi:10.1002/humu.24179

Cited by 15 publications

(18 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, while in the mouse knockouts the observed phenotype is most likely due to the loss of protein function, other types of mutation may lead to different molecular mechanisms and thus different phenotypic outcomes. True loss of protein function in these genes may be early embryonic lethal in humans whereas postnatal phenotypes could be caused by hypomorphic variants leading to partial LoF 58,59 . Other explanations include potential mechanisms of compensation through other genes in the pathway in humans or differences in essentiality between the two species.…”

Section: Discussionmentioning

confidence: 99%

Mendelian gene identification through mouse embryo viability screening

Cacheiro

Westerberg

Mager

et al. 2022

Preprint

View full text Add to dashboard Cite

The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease. Based on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.

show abstract

Section: Discussionmentioning

confidence: 99%

Mendelian gene identification through mouse embryo viability screening

Cacheiro

Westerberg

Mager

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“… 53 Variants in the aldehyde dehydrogenase 1 family member A2 ( ALDH1A2 ) gene cause lethal multiple congenital anomaly syndrome. 54 ATPase copper transporting alpha (ATP7A) is a critical copper transporter involved in some X linked genetic disorders, such as Menkes disease, occipital horn syndrome and type 3 X‐linked distal spinal muscular atrophy. 55 Protocadherin related 15 ( PCDH15 ) is associated with nonsyndromic deafness and type 1 Usher syndrome.…”

Section: Discussionmentioning

confidence: 99%

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

Zhang

Huang

et al. 2021

The Journal of Gene Medicine

View full text Add to dashboard Cite

Background: The present study aimed to explore the etiological relationship between miscarriage and stillbirth and copy number variations (CNVs), as well as provide useful genetic guidance for high-risk pregnancy.Methods: In total, 659 fetal samples were recruited and subjected to DNA extraction and CNV sequencing (CNV-seq), relevant medical records were collected.Results: There were 322 cases (48.86%) with chromosomal abnormalities, including 230 with numerical abnormalities and 92 with structural abnormalities. Chromosomal monosomy variations mainly occurred on sex chromosomes and trisomy variations mainly occurred on chromosomes 16, 22, 21, 18, 13 and 15. In total, 41 pathogenic CNVs (23 microdeletions and 18 microduplications) were detected in 27 fetal tissues.The rates of numerical chromosomal abnormalities were 29.30% (109/372), 32.39% (57/176) and 57.66% (64/111) in < 30-year-old, 30-34-year-old and ≥ 35-year-old age pregnant women, respectively, and increased with an increasing age (p < 0.001).There was statistically significant difference (χ 2 = 7.595, p = 0.022) in the rates of structural chromosomal abnormalities in these groups (13.71%, 18.75% and 7.21%, respectively). The rates of numerical chromosomal abnormalities were 45.44% (219/482), 7.80% (11/141) and 0% (0/36) in the ≤ 13 gestational weeks, 14-27 weeks and ≥ 28 weeks groups, respectively, and decreased with respect to the increasing gestational age of the fetuses (p < 0.001). Conclusions:The present study has obtained useful and accurate genetic etiology information that will provide useful genetic guidance for high-risk pregnancies.

show abstract

“…The chr15: 58284941; NM_003888.3: c.759delC; p.(H253Qfs * 4) variant results in a frameshift and predicted truncation of the 518 amino acid protein after amino acid 257 and was inherited from the mother. The chr15: 58256129; NM_003888.3: c.1040G > A; p.(Arg347His) variant was inherited from the father and was previously identified in another family (Beecroft et al, 2021). Targeted familial variant gene analysis was performed on subject 3 which identified the two ALDH1A2 variants; see pedigree in Figure 3a.…”

Section: Case Reports and Laboratory Resultsmentioning

confidence: 93%

ALDH1A2‐related disorder: A new genetic syndrome due to alteration of the retinoic acid pathway

Leon

Nde

Ray

et al. 2022

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Aldehyde Dehydrogenase 1, Family Member A2 (ALDH1A2) is essential for the synthesis of retinoic acid from vitamin A. Studies in model organisms demonstrate a critical role for ALDH1A2 in embryonic development, yet few pathogenic variants are linked to congenital anomalies in humans. We present three siblings with multiple congenital anomaly syndrome linked to biallelic sequence variants in ALDH1A2. The major congenital malformations affecting these children include tetralogy of Fallot, absent thymus, diaphragmatic eventration, and talipes equinovarus. Upper airway anomalies, hypocalcemia, and dysmorphic features are newly reported in this manuscript. In vitro functional validation of variants indicated that substitutions reduced the expression of the enzyme. Our clinical and functional data adds to a recent report of biallelic ALDH1A2 pathogenic variants in two families with a similar constellation of congenital malformations. These findings provide further evidence for an autosomal recessive ALDH1A2‐deficient recognizable malformation syndrome involving the diaphragm, cardiac and musculoskeletal systems.

show abstract

Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects

Cited by 15 publications

References 67 publications

Mendelian gene identification through mouse embryo viability screening

Mendelian gene identification through mouse embryo viability screening

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

ALDH1A2‐related disorder: A new genetic syndrome due to alteration of the retinoic acid pathway

Contact Info

Product

Resources

About