Open Access

A novel exomal ATRX mutation with preferential transmission to offspring: A case report and review of the literature for transmission ratio distortion in ATRX families

  • Authors:
    • Mariano Stabile
    • Davide Colavito
    • Elda Del Giudice
    • Anna F. Rispoli
    • Marina C. Ingenito
    • Anna K. Naumova
  • View Affiliations

  • Published online on: October 9, 2020     https://doi.org/10.3892/mmr.2020.11574
  • Pages: 4561-4566
  • Copyright : © Stabile et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

The present case report describes an Italian family with three affected probands, who exhibited serious mental disability, which has not been associated with other anomalies, except with slight facial dysmorphism. Molecular multigenic analysis for intellectual disability identified a previously unreported variant, p.Ile1765Met (c.5295C>G) in the SNF domain of the ATRX protein (in exon 24). The identified mutation was found in a hemizygous state in all three affected probands and in a heterozygous state in the asymptomatic mother and the female sibling. With respect to the phenotypic similarities found in the patients with those described in previous studies, the consistency in the mode of inheritance and segregation of the mutation, the variant reported in the present case report may be considered as ‘likely pathogenic’. To investigate the hypothesis that the preferential transmission of the ATRX mutation observed in this family reflected a general trend, a meta‑analysis into the segregation of ATRX mutations from published pedigrees, following allelic transmission from mothers who are heterozygous carriers to their offspring, was performed. A preferential transmission of the mutant allele to male offspring (58% of males inherited the mutant allele) was found; however, the bias was not statistically significant (P=0.29; χ2 test).

Introduction

X-linked mental disability (MRX) is a form of intellectual disability (ID) associated with the X chromosome. It is one of the most frequent forms of ID with an incidence rate of 3% in the human population.

One of the X-linked loci associated with MRX is the α thalassemia X-linked intellectual disability (ATRX) gene (OMIM #301040; Xq21.1); characterized by a complex phenotype and the primary elements consist of a serious impairment of psychomotor development, facial dysmorphism, genital anomalies and α thalassemia. Inherited mutations of ATRX are associated with an X-linked mental disability syndrome (XLMR), and the majority of cases also have α-thalassemia syndrome (ATR-X). ATRX syndrome, which has been associated with ATRX mutations is characterized by a complex phenotype, including serious impairment of psychomotor development, facial dysmorphism, genital anomalies and α thalassemia (1). Female carriers of ATRX mutations are intellectually normal and rarely show physical manifestations, due to an extreme skewing of X-inactivation in favor of the chromosome containing the non-mutant allele (1). There are >200 cases of ATR-X syndrome that have been identified using molecular diagnostics (25).

ATRX encodes a protein, consisting of 2,492 amino acids. It has multiple functions, including regulation of transcription, chromatin remodeling and ATP-dependent helicase activity (https://www.uniprot.org/uniprot/P46100). Alternative splicing of the gene results in distinct protein isoforms.

The protein has two primary functional domains, the N-terminal ADD domain and the C-terminal helicase/adenosine triphosphatase domain (ATPase), where the majority of reported mutations are located. Most of the reported mutations are missense, with c.536A>G and c.736C>T, both in the ADD domain, being the most common mutations found in different families. Mutations in the ADD domain are associated with greater impairment of psychomotor development, while most cases with mild/moderate mental disability have mutations in the helicase domain. The common mutation, c.736C>T, has been associated with low frequency of Hemoglobin H HbH (6).

In the present case report, a novel, likely pathogenic, ATRX variant c.5295C>G associated with mental disability has been identified. The family in the report shows a strong transmission bias in favor of the mutant allele: All 4 offspring inherited the mutant ATRX allele from their mother.

Case report

Whole blood (3 ml) was collected for exome analysis after informed consent was provided. DNA was extracted using the Qiagen BioRobot DNA extraction kit (Qiagen Benelux B.V.) according to the manufacturer's instructions and quantified using NanoDrop spectral analysis (Thermo Fischer Scientific, Inc.). DNA integrity was evaluated using standard agarose gel electrophoresis (100 V; 30 min; 1.5% agarose gel in TBE buffer). DNA library preparation and whole exon enrichment were performed using Agilent All Exon V.6 kit (Agilent Technologies, Inc.). The library was sequenced using the HiSeq2500 Illumina Sequencer (125-bp paired end sequence mode; Illumina, Inc.). Bioinformatics analysis included the following: i) Next generation sequencing reads were mapped to whole genomes using the Burrows-Wheeler Alignment tool with the default parameters, ii) PCR duplicate removal using Picard (http://picard.sourceforge.net), iii) identification of single nucleotide polymorphisms and insertions/deletions using the Genome Analysis Toolkit (GATK) UnifiedGenotyper, iv) variant annotation using snpEff (http://snpeff.sourceforge.net) and v) false positive variant filtration using the GATK VariantFiltration module. Exome sequencing data and read alignment analysis was checked for coverage depth and alignment quality using the Bedtools software package. Variant classification was performed in accordance with the guidelines from the American College of Medical Genetics and Genomics (ACMG).

Phenotype driven analysis coupled with the employment of in silico multigene panels specific for ID and neurodevelopmental disorders was used to filter, select and interpret genetic variants obtained following exome sequencing. The presence of significant variants was confirmed using Sanger sequencing.

Clinical description

In the Italian family A (Fig. 1) with healthy and non-consanguineous parents (I-1 and I-2), all three male probands (II-1, II-2, II-3) showed medium to severe mental disability and mild dysmorphism, while the heterozygous females (I-2 and II-4) are phenotypically and intellectually normal. The mother was 16, 18, 32 and 35-years-old when all of her children were born, respectively. The family history was unremarkable for ID or birth defects. In the mother's family, the male sibling was intellectually normal, as were the seven nephews born to the three female siblings (data not shown).

The three affected male probands have a similar clinical history and phenotype with greater intellectual impairment in one of the probands. They were delivered at term by caesarean section, following an uneventful pregnancy. Their birth weights were 3,200, 3,000, and 3,050 g for II-1, II-2 and II-3, respectively. The auxological parameters were within the limits of the normal range, while gross motor, cognitive and social milestones were delayed in early childhood. None of the probands had epileptic seizures. With respect to the characteristics associated with the pathology of ATRX syndrome, specific signs of facial dysmorphism (facial hypotonia and hypertelorism) were absent, while other signs (mouth ‘carp’ and depressed nasal bridge) were present. However, genital anomalies (cryptorchidism and/or ambiguous genitalia), epileptic seizures, autistic behavior, and α-thalassemia (microcytic anemia and Heinz bodies) were absent.

The first-born, II-1 (48 years old) lives at home with his family. Currently, the patient is autonomous in his movements. Partial presence of linguistic acquisitions and gestural communication is also present. The patient is very calm and has no problems with breathing or swallowing. There are no ‘snap’ movements of the upper limbs and enjoys care and physical contact. The other two probands have been hospitalized at a facility. The cranial magnetic resonance imaging performed on II-1 revealed cerebral hypoplasia without signs of cortical dysplasia, important dilatation of the subarachnoid spaces in the temporal and frontal regions, and large cisternal spaces in front of the trunk.

The second born, II-2 (46 years old) is the most intellectually and neurologically compromised. He does not control sphincters and physiological stimuli, and has no linguistic acquisition and gestural communication. Therefore, assessment of his intellectual level is not possible.

The youngest of the three male siblings, II-3 (32 years old) presents acquisition of language and gestural communication, as well as learning related to social and relational skills.

Laboratory analysis

The standard karyotypes of all the patients were normal. Fragile X screening, which was performed in the mother, all 3 male probands and the female sibling highlighted the presence of two alleles with values in the normal range. Genome analysis using the comparative genomic hybridization-array technique with SurePrintG3 ISCA V2 GCH60K microarrays (Cytogenomics v3.0.0.019; Agilent Technologies, Inc.) was performed on the mother and one of the probands (II-2). No imbalances in the number of copies of the analyzed genomic sequences, i.e. no deletions or duplications, were detected (data not shown).

Sequencing analysis of the coding exons of the genes included in the genetic panel for the molecular diagnosis of ID and neurodevelopmental disorders showed the presence of the hemizygous variant, c.5295C>G (resulting in the amino acid change p.Ile1765Met) in the ATRX gene in all three probands, while the unaffected mother and female sibling were heterozygous carriers of this variant.

This mutation was not present in allele frequency databases (ExAC, EVS and GnomeAD). Bioinformatics predictors indicate that isoleucine at position 1,765 is highly conserved through higher vertebrates (PhyloP-Primates, 2.70/6.42; PhyloP-Primate, 0.60/0.65) and the missense change, isoleucine to methionine is likely to be deleterious (Polyphen2, 1.00/1.00; SIFT, 0.001/0.00; CADD-Phred, 18). The analysis of the quaternary structure of the protein (pfam database) showed that the novel mutation, at position 1,765, falls within the SNF2 N helicase domain (Table I) located between the ADD and the helicase C domains. The SNF domain is found in proteins involved in a variety of different functions, including transcriptional regulation, recombination, and DNA repair (7).

Table I.

Table pfam domains.

Table I.

Table pfam domains.

SourceDomainStartEnd
Disordern/a1159
Low_complexityn/a2433
Low_complexityn/a5983
Low_complexityn/a103114
PfamADD ATRX158213
Disordern/a311312
Disordern/a415440
Disordern/a445581
Disordern/a586588
n/an/an/an/a
n/an/an/an/a
n/an/an/an/a
PfamSNF 2 N15361889a
Disordern/a15441545
Disordern/a15511553
Low_complexityn/a19121925
Disordern/a19131915
n/an/an/an/a
n/an/an/an/a
n/an/an/an/a
PfamHelicase C20182155
Disordern/a22182229
Disordern/a22542266
Low_complexityn/a22612269
Low_complexityn/a22672282
n/an/an/an/a
n/an/an/an/a
n/an/an/an/a
Low_complexityn/a24662479

{ label (or @symbol) needed for fn[@id='tfn1-mmr-22-06-4561'] } The table provides domain boundaries for the ATRX protein.

a Amino acid substitution in the SNF 2N domain in the family A. SNF, Sucrose Non-Fermentable. n/a, not applicable.

Therefore, in the absence of further information, and in agreement with guidelines by ACMG (2015), the mutation should be considered of uncertain significance. We propose that, based on the overlap within the phenotypes of the probands, with those previously described, the concordance with the mode of inheritance, together with the result of the analysis of family segregation, the variant p.Ile1765Met (c.5295C>G) reported in the present study and found in a hemizygous state in all the affected subjects of the same family, may be considered ‘likely pathogenic’.

Meta-analysis of maternal transmission of ATRX mutations

Family A shows a striking bias in favor of transmission of the mutant allele from the mother who is a carrier to all four of her living children. Such bias may be due to i) a preferential transmission of mutant ATRX alleles; ii) the presence of a deleterious mutation on the X chromosome that carries the non-mutant ATRX allele in the mother; or iii) it could be purely stochastic.

To investigate the possibility that mutant ATRX alleles were preferentially transmitted to offspring, a meta-analysis of published pedigrees with complete reporting of family structures was conducted. Data on transmission of ATRX alleles for 42 mothers were extracted from papers published between 1991 and 2019 (821). Probands and index cases were excluded from the calculations, as well as offspring from one mosaic mother. A modest bias was found in favor of ATRX mutations being transmitted to male offspring. Among the total of 127 offspring, 54% inherited the mutation, while 58% of the 70 males inherited the mutant allele. However, the bias did not reach statistical significance (P=0.29; χ2 test). All data from families with ATRX were analyzed using the chi square test (χ2 test). A chi-square test is a statistical hypothesis test, used to determine whether there is a statistically significant difference between the expected frequencies and the observed frequencies in one or more categories of a contingency table. The chi-square test applied to our sample was P=0.29, which does not reach statistical significance.

Next, the analysis was limited to a subset of families where the mutations were identified, and all members of the family were genotyped (Table II) (812,1417). A modest sex-ratio distortion was observed in favor of the male offspring, as well as transmission-ratio distortion in favor of the ATRX mutant alleles, but these did not reach statistical significance either (Table II).

Table II.

Meta-analysis of ATRX allele transmission from carrier mother to offspring in families with confirmed mutations.

Table II.

Meta-analysis of ATRX allele transmission from carrier mother to offspring in families with confirmed mutations.

SonsDaughters


No.MutationPedigreeMotherCarrierNon-carrierCarrierNon-carrierProband/index Caseexcluded Authors/(Refs.)
1c.5295C>G 2010YesCurrent report
2c.6130C>T 1000YesAltiner and Raymond 2019 (9)
3c.515C>T II-10010 Li et al 2020 (14)
4c.6257T >C3III-11000 Yan et al 2019 (21).
5c.6257T >C3III-41001 Yan et al 2019 (21)
6c.6718C>T 1000YesThakur et al 2011 (17)
7c.6740A>C 0020YesBouazzi et al 2016 (11)
8c.109C>TK8035I-21420 Basehore et al 2015 (10)
9c.109C>TK8035II-12211 Basehore et al 2015 (10)
10c.109C>TK8035III-11211 Basehore et al 2015 (10)
11c.109C>TK8035II-41001YesBasehore et al 2015 (10)
12c.109C>TK8360I-22221YesBasehore et al 2015 (10)
13c.109C>TK8360II-31000 Basehore et al 2015 (10)
14c.109C>TK8820I-24411 Basehore et al 2015 (10)
15c.109C>TK8820II-101101YesBasehore et al 2015 (10)
16c.109C>TK9574/MRX77II-21150 Basehore et al 2015 (10)
17c.109C>TK9574/MRX77III-11002 Basehore et al 2015 (10)
18c.109C>TK9574/MRX77III-31010 Basehore et al 2015 (10)
19c.109C>TK9574/MRX77III-42000 Basehore et al 2015 (10)
20c.109C>TK9574/MRX77III-50101 Basehore et al 2015 (10)
21c.109C>TK9574/MRX77III-62000 Basehore et al 2015 (10)
22c.109C>TJHH2445-6 1000YesBasehore et al 2015 (10)
23c.109C>T II1000YesMoncini et al 2013 (16)
24c.109C>T IV-20110YesAbidi et al 2005 (8)
25c.7156C>T 0101YesMasliah-Planchon et al
Total 28201811 2018 (15)

[i] Excess of male offspring (sex-ratio distortion) and mutation carriers (transmission-ratio distortion) is noted, but neither reach statistical significance: P=0.055 for sex-ratio distortion, P=0.087 for transmission-ratio distortion, χ2 test.

It was proposed that the non-mutant X chromosome of the mother in family A was affected by a deleterious aberration limiting its transmission to offspring. However, no evidence of deletions or duplications, or X-autosomal translocations were found. Nevertheless, the possibility that she carries an unidentified deleterious mutation on the chromosome harboring the non-mutant ATRX allele cannot be ruled out.

Discussion

The ATRX gene encodes a protein that belongs to the SNF2 chromatin remodeling protein family. Members of this large family of proteins modify the accessibility of DNA wrapped around a nucleosome, ensuring the nucleic acid is more or less accessible to proteins, which regulate the transcription process. To date, the exact role of ATRX is still under debate (22). ATRX contains two highly conserved domains, namely the ADD domain at the N-terminus and a C-terminal ATPase/helicase domain, the latter is involved in ATP hydrolysis. The ADD domain was named ARTX-DNMT3-DNMT3L, based on the sequence homology with a family of DNA methyltransferases. Argentaro et al (7) reported the solution structure of the ADD domain of ARTX, which consisted of an N-terminal GATA-like zinc finger, a plant homeodomain (PHD), and a long C-terminal α-helix. All the pathogenic mutations associated with X-linked mental disability map to the ADD and helicase domains.

In the present case report, a novel, likely pathogenic, missense mutation located in exon 24 of the major splice form of ATRX was identified. The novel p.lle1765Met variant changes the amino acid sequence of the SNF2 N helicase domain in the protein. This region is often affected by mutations associated with ATRX syndrome (23). Methionine is an α-amino acid and termed as a non-polar, aliphatic amino acid due to the S-methyl thioether side chain. Isoleucine is a non-polar, uncharged (at physiological pH) aliphatic amino acid with a branched chain. Isoleucine and methionine are both non-polar amino acids; however, due to their different structures, a modification of the tertiary structure and function of the SNF2 N domain cannot be excluded. The novel pIle1765Met mutation is also close to the highly conserved ATPase active site motif III. Another mutation, Leu1746Ser, which is located very close but outside of motif III, has been shown to uncouple the ATPase activity of ATRX from its ability to bind and translocate along DNA (23). In in vitro experiments, the mutant Leu1746Ser was more efficient at hydrolyzing ATP compared with that in the wild type variant, but failed to displace the third DNA strand in the triple helix displacement assay (23).

Considering the family tree of family A, a notable observation is that the ATRX mutation was transmitted to all four offspring from the carrier mother, while the composite probability of such a transmission is only 6.25%. We therefore hypothesized if the mutant ATRX allele was more likely to be transmitted to offspring by carrier mothers and conducted a meta-analysis of the segregation of ATRX mutations in published pedigrees (Table II). There was a tendency towards preferential transmission of the mutant allele to male offspring (58% of males inherited the mutant allele); however, the bias was not statistically significant (P=0.29, χ2 test). The transmission-ratio distortion and its underlying mechanisms are still poorly understood, with explanations ranging from meiotic drive (alleles preferentially retained in the oocyte vs. the polar body) to differences in embryo survival (2426). It is worth noting that ATRX is essential for oogenesis and its loss affects normal chromosome segregation (27). However, even without full understanding of the underlying mechanisms, preferential transmission of mutant alleles may be an important aspect to be considered in genetic counseling.

Acknowledgements

Not applicable.

Funding

The current study was supported by the ‘Zigote Center’ and by ‘Research & Innovation srl’.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

MS contributed in conceiving and designing the study; DC and EDG performed the sequencing analysis, AFR and MCI performed standard and molecular cytogenetics. AKN contributed in meta-analysis of maternal transmission of ATRX mutations and conducted χ2 test. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

The guardian of the patient provided written informed consent for the publication of any associated data.

Competing interests

The authors declare that they have no competing interests.

References

1 

Gibbons RJ, Brueton L, Buckle VJ, Burn J, Clayton-Smith J, Davison BC, Gardner RJ, Homfray T, Kearney L, Kingston HM, et al: Clinical and hematologic aspects of the X-linked alpha-thalassemia/mental disability syndrome (ATR-X). Am J Med Genet. 55:288–299. 1995. View Article : Google Scholar : PubMed/NCBI

2 

Gibbons RJ: Alpha thalassaemia-mental disability, X linked. Orphanet J Rare Dis. 4:15Review2006. View Article : Google Scholar

3 

Stevenson RE: Alpha-Thalassemia X-linked Intellectual Disability Syndrome. GeneReviews((R). Adam MP, Ardinger HH and Pagon RA: University of Washington; Seattle, WA: 1993

4 

Stevenson RE: Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. 2000 Jun 19 [Updated 2020 May 28]. GeneReviews® [Internet]. Adam MP, Ardinger HH, Pagon RA, et al: University of Washington; Seattle, WA: 1993-2020, simplehttps://www.ncbi.nlm.nih.gov/books/NBK1449/February 5–2020

5 

Garber KB, Warren ST and Visootsak J: Chapter 107-Fragile X Syndrome and X-linked intellectual disability. Emery and Rimoin's Principles and Practice of Medical Genetics (6th edition). Rimoin. 1–27. 2013. View Article : Google Scholar

6 

Lin SB, Sun HY, Song XM, Chen LM, Du ML and Chen Z: Mutation analysis for a Chinese family featuring X-linked alpha thalassemia/mental disability syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 654–658. 2013.(In Chinese). PubMed/NCBI

7 

Argentaro A, Yang JC, Chapman L, Kowalczyk MS, Gibbson RJ, Higgs DR, Neuhaus D and Rhodes D: Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX. Proc Natl Acad Sci USA. 104:11939–11944. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Abidi FE, Cardoso C, Lossi AM, Lowry RB, Depetris D, Mattéi MG, Lubs HA, Stevenson RE, Fontes M, Chudley AE and Schwartz CE: Mutation in the 5′ alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. Eur J Hum Genet. 13:176–183. 2005. View Article : Google Scholar : PubMed/NCBI

9 

Altiner Ş and Raymond L: A novel ATRX mutation presenting with intellectual disability and severe kyphoscoliosis. Fetal Pediatr Pathol. 1–5. 2019. View Article : Google Scholar : PubMed/NCBI

10 

Basehore MJ, Michaelson-Cohen R, Levy-Lahad E, Sismani C, Bird LM, Friez MJ, Walsh T, Abidi F, Holloway L, Skinner C, et al: Alpha-thalassemia intellectual disability: Variable phenotypic expression among males with a recurrent nonsense mutation-c.109C>T (p.R37X). Clin Genet. 87:461–466. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Bouazzi H, Thakur S, Trujillo C, Alwasiyah MK and Munnich A: Novel ATRX gene damaging missense mutation c.6740A>C segregates with profound to severe intellectual deficiency without alpha thalassemia. Indian J Med Res. 143:43–48. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Hamzeh AR, Nair P, Mohamed M, Saif F, Tawfiq N, Al-Ali MT and Bastaki F: A novel missense mutation in ATRX uncovered in a Yemeni family leads to alpha-thalassemia/mental disability syndrome without alpha-thalassemia. Ir J Med Sci. 186:333–337. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Ion A, Telvi L, Chaussain JL, Galacteros F, Valayer J, Fellous M and McElreavey K: A novel mutation in the putative DNA helicase XH2 is responsible for male-to-female sex reversal associated with an atypical form of the ATR-X syndrome. Am J Hum Genet. 58:1185–1191. 1996.PubMed/NCBI

14 

Li L, Yu J, Zhang X, Han M, Liu W, Li H and Liu S: A novel ATRX mutation causes SmithFinemanMyers syndrome in a Chinese family. Mol Med Rep. 21:387–392. 2020.PubMed/NCBI

15 

Masliah-Planchon J, Lévy D, Héron D, Giuliano F, Badens C, Fréneaux P, Galmiche L, Guinebretierre JM, Cellier C, Waterfall JJ, et al: Does ATRX germline variation predispose to osteosarcoma? Three additional cases of osteosarcoma in two ATR-X syndrome patients. Eur J Hum Genet. 26:1217–1221. 2018. View Article : Google Scholar : PubMed/NCBI

16 

Moncini S, Bedeschi MF, Castronovo P, Crippa M, Calvello M, Garghentino RR, Scuvera G, Finelli P and Venturin M: ATRX mutation in two adult brothers with non-specific moderate intellectual disability identified by exome sequencing. Meta Gene. 1:102–108. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Thakur S, Ishrie M, Saxena R, Danda S, Linda R, Viswabandaya A and Verma IC: ATR-X syndrome in two siblings with a novel mutation (c.6718C>T mutation in exon 31). Indian J Med Res. 134:483–486. 2011.PubMed/NCBI

18 

Villard L, Toutlain A, Lossi AM, Gecz J, Houdayer C, Moraine C and Fontès M: Splicing mutation in the ATR-X gene can lead to a dysmorphic mental disability phenotype without alpha-thalassemia. Am J Hum Genet. 58:499–505. 1996.PubMed/NCBI

19 

Villard L, Fontés M, Adès LC and Gecz: Identification of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers syndrome. Am J Med Genet. 91:83–85. 2000. View Article : Google Scholar : PubMed/NCBI

20 

Wilkie AO, Gibbons RG, Higgs DR and Pembrey ME: X linked alpha thalassaemia/mental disability: Spectrum of clinical features in three related males. J Med Genet. 28:738–741. 1991. View Article : Google Scholar : PubMed/NCBI

21 

Yan H, Shi Z, Wu Y, Xiao J, Gu Q, Yang Y, Li M, Gao K, Chen Y, Yang X, et al: Targeted next generation sequencing in 112 Chinese patients with intellectual disability/developmental delay: Novel mutations and candidate gene. BMC Med Genet. 20:802019. View Article : Google Scholar : PubMed/NCBI

22 

Dyer MA, Qadeer ZA, Valle-Garcia D and Bernstein E: ASTRX and DAXX: Mechanisms and mutation. Cold Spring Harb Perspect Med. 7:a0265672017. View Article : Google Scholar : PubMed/NCBI

23 

Mitson M, Kelley LA, Sternberg MJ, Higgs DR and Gibbson RJ: Functional significance of mutations in the Snf2 domain of ATRX. Hum Mol Genet. 20:2603–2610. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Naumova AK, Greenwood CM and Morgan K: Imprinting and deviation from Mendelian transmission ratios. Genome. 44:311–320. 2001. View Article : Google Scholar : PubMed/NCBI

25 

Huang LO, Labbe A and Infante-Rivard C: Transmission ratio distortion: Review of concept and implications for genetic association studies. Hum Genet. 132:245-263. 2013. View Article : Google Scholar

26 

LeMair-Adkins R and Hunt PA: Nonrandom segregation of the mouse univalent X chromosome: Evidence of spindle-mediated meiotic drive. Genetics. 156:775–783. 2000.PubMed/NCBI

27 

De La Fuente R, Baumann C and Viveiros MM: Chromatin structure and ATRX function in mouse oocytes. Results Probl Cell Differ. 55:45–68. 2012. View Article : Google Scholar : PubMed/NCBI

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Stabile M, Colavito D, Del Giudice E, Rispoli AF, Ingenito MC and Naumova AK: A novel exomal ATRX mutation with preferential transmission to offspring: A case report and review of the literature for transmission ratio distortion in ATRX families. Mol Med Rep 22: 4561-4566, 2020
APA
Stabile, M., Colavito, D., Del Giudice, E., Rispoli, A.F., Ingenito, M.C., & Naumova, A.K. (2020). A novel exomal ATRX mutation with preferential transmission to offspring: A case report and review of the literature for transmission ratio distortion in ATRX families. Molecular Medicine Reports, 22, 4561-4566. https://doi.org/10.3892/mmr.2020.11574
MLA
Stabile, M., Colavito, D., Del Giudice, E., Rispoli, A. F., Ingenito, M. C., Naumova, A. K."A novel exomal ATRX mutation with preferential transmission to offspring: A case report and review of the literature for transmission ratio distortion in ATRX families". Molecular Medicine Reports 22.6 (2020): 4561-4566.
Chicago
Stabile, M., Colavito, D., Del Giudice, E., Rispoli, A. F., Ingenito, M. C., Naumova, A. K."A novel exomal ATRX mutation with preferential transmission to offspring: A case report and review of the literature for transmission ratio distortion in ATRX families". Molecular Medicine Reports 22, no. 6 (2020): 4561-4566. https://doi.org/10.3892/mmr.2020.11574