Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?

Shoubridge, Cheryl; Gardner, Alison; Schwartz, Charles E.; Hackett, Anna; Field, Michael; Gécz, Jozef

doi:10.1038/ejhg.2012.61

Cited by 9 publications

(6 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although a rare phenomenon, TRD has already been described in other autosomal dominant disorders such as the long‐QT syndrome and trinucleotide repeat expansions, but also in recessive and X‐linked disorders . Similar transmission ratios were found: 57% for the long‐QT syndrome, 63% for myotonic dystrophy, 60% for mutations on the ARX gene …”

Section: Discussionsupporting

confidence: 54%

Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations

Snanoudj

Molin

Colson

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted Guanine Nucleotide Binding Protein, Alpha Stimulating Activity (GNAS) gene, coding G s α. PHP1A is caused by mutations in the maternal allele and results in Albright's hereditary osteodystrophy (AHO) and hormonal resistance, mainly to the parathormone (PTH), whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a population of 204 families with 361 patients harboring GNAS mutations. To prevent ascertainment bias toward a higher proportion of affected children due to the way in which data were collected, we excluded from transmission analysis all probands in the ascertained sibships. After bias correction, the distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample Z-test). Sex ratio, phenotype of the transmitting parent, and transmission depending on the severity of the mutation were also analyzed. Transmission analysis was performed in 114 nuclear families and included 250 descendants. The fertility rates were similar between male and female patients. We showed an excess of transmission from mother to offspring of mutated alleles (59%, p = .022), which was greater when the mutations were severe (61.7%, p = .023). Similarly, an excess of transmission was found when the mother had a PHP1A phenotype (64.7%, p = .036). By contrast, a Mendelian distribution was observed when the mutations were paternally inherited. Higher numbers of females within the carriers, but not in noncarriers, were also observed. The motherspecific transmission ratio distortion (TRD) and the sex-ratio imbalance associated to PHP1A point to a role of G s α in oocyte biology or embryogenesis, with implications for genetic counseling.

show abstract

Section: Discussionsupporting

confidence: 54%

Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations

Snanoudj

Molin

Colson

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…Another human mutation that has been reported to show a TRD is a polyalanine expansion in the ARX ( Aristaless-related homeobox gene ) transcription factor coding-gene located on the X chromosome [ 141 ]. This gene plays important roles in brain development and is associated with several neurodevelopmental diseases depending on the severity of the mutations [ 142 ].…”

Section: Transmission Biases Reported In Human and In Pathologiesmentioning

confidence: 99%

“…Heterozygous females have no phenotype. Interestingly, clinicians have noted an excess number of affected males among the offspring of carrier females, raising the possibility of a TRD for this mutation ([ 141 , 143 ]). However, further studies were hampered by the relatively small number of affected families in the world and by their small size.…”

Section: Transmission Biases Reported In Human and In Pathologiesmentioning

confidence: 99%

Bypassing Mendel’s First Law: Transmission Ratio Distortion in Mammals

Friocourt

Perrin

Saunders

et al. 2023

IJMS

View full text Add to dashboard Cite

Mendel’s law of segregation states that the two alleles at a diploid locus should be transmitted equally to the progeny. A genetic segregation distortion, also referred to as transmission ratio distortion (TRD), is a statistically significant deviation from this rule. TRD has been observed in several mammal species and may be due to different biological mechanisms occurring at diverse time points ranging from gamete formation to lethality at post-natal stages. In this review, we describe examples of TRD and their possible mechanisms in mammals based on current knowledge. We first focus on the differences between TRD in male and female gametogenesis in the house mouse, in which some of the most well studied TRD systems have been characterized. We then describe known TRD in other mammals, with a special focus on the farmed species and in the peculiar common shrew species. Finally, we discuss TRD in human diseases. Thus far, to our knowledge, this is the first time that such description is proposed. This review will help better comprehend the processes involved in TRD. A better understanding of these molecular mechanisms will imply a better comprehension of their impact on fertility and on genome evolution. In turn, this should allow for better genetic counseling and lead to better care for human families.

show abstract

“…In some studies, case and control populations were analyzed separately to detect a difference in transmission (Friedrichs et al, 2006 ; Shoubridge et al, 2012 ). To address the possible presence of TRD in the studied population, Spielman et al ( 1993 ) analyzed both case/control-trios separately using the TDT.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Case-Parent Trios Using a Loglinear Model with Adjustment for Transmission Ratio Distortion

2016

View full text Add to dashboard Cite

Transmission of the two parental alleles to offspring deviating from the Mendelian ratio is termed Transmission Ratio Distortion (TRD), occurs throughout gametic and embryonic development. TRD has been well-studied in animals, but remains largely unknown in humans. The Transmission Disequilibrium Test (TDT) was first proposed to test for association and linkage in case-trios (affected offspring and parents); adjusting for TRD using control-trios was recommended. However, the TDT does not provide risk parameter estimates for different genetic models. A loglinear model was later proposed to provide child and maternal relative risk (RR) estimates of disease, assuming Mendelian transmission. Results from our simulation study showed that case-trios RR estimates using this model are biased in the presence of TRD; power and Type 1 error are compromised. We propose an extended loglinear model adjusting for TRD. Under this extended model, RR estimates, power and Type 1 error are correctly restored. We applied this model to an intrauterine growth restriction dataset, and showed consistent results with a previous approach that adjusted for TRD using control-trios. Our findings suggested the need to adjust for TRD in avoiding spurious results. Documenting TRD in the population is therefore essential for the correct interpretation of genetic association studies.

show abstract

Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?

Cited by 9 publications

References 46 publications

Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations

Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations

Bypassing Mendel’s First Law: Transmission Ratio Distortion in Mammals

Analysis of Case-Parent Trios Using a Loglinear Model with Adjustment for Transmission Ratio Distortion

Contact Info

Product

Resources

About