Skip to main content
NCBI home page
Molecular Genetics & Genomic Medicine logoLink to Molecular Genetics & Genomic Medicine
. 2024 Jun 21;12(6):e2484. doi: 10.1002/mgg3.2484

Parental mosaicism rather than de novo variants in FOXG1 ‐related syndrome and TUBA1A ‐associated Tubulinopathy: Familial case reports

Hai Xuan Tang 1, Y‐Thanh Lu 2, Thi Minh Thi Ha 3, Nhat‐Thang Tran 4, Doan Minh Dang 5, Son Xuan Ly 5, Thu Ha Thi Bui 5, Son Ta Vo 6, Minh Doan Thai 7, Vu Dinh Nguyen 8, Thong Van Nguyen 8, Linh Thuy Dinh 9, Lan‐Anh Thi Luong 10, Kim‐Phuong Doan 10, Kim Huong Thi Nguyen 2, Thanh‐Thuy Thi Do 2, Dinh‐Kiet Truong 2, Hoa Giang 2, Hoai‐Nghia Nguyen 2, Thu Huong Nhut Trinh 5,✉, Hung Sang Tang 2,✉
PMCID: PMC11192965

Abstract

Background

De novo variations are a primary cause of Rett syndrome and Tubulinopathy, accounting for over 90% of cases. Some studies have identified and documented parental inheritance by mosaicism in these two disorders, albeit with limited data.

Methods

Clinical characteristics and diagnosis, including genetic tests of members of two families, were obtained from medical reports.

Results

The first family with Rett syndrome (RTT) presented with two offspring carrying FOXG1 c.460dup. Both affected RTT pregnancies did not show anomalies within the first trimester, preventing prenatal recognition at an early stage. The second family had two of three offspring confirmed with TUBA1A c.172G>A related to Tubulinopathy. Both young couples from the two families harbored none of the variants correlating to their children's conditions. Diagnosis of parental mosaics with higher rates of recurrence was reasonably determined, and genetic counseling played a major role in guiding and managing their subsequent pregnancies.

Conclusion

In genetic disorders with a high penetration of de novo variants, the risk of having a recurrent baby is an important topic to discuss with affected families. By examining variants that siblings share, clinical diagnosis can offer valuable information about the presence of mosaic inheritance. To effectively manage in the long term, adequate genetic counseling and strategic planning for future pregnancies should be emphasized to mitigate the risk of recurrent offspring.

Keywords: FOXG1, mosaicism, Rett syndrome, TUBA1A, Tubulinopathy

1. INTRODUCTION

De novo variants account for 48%–63% of deleterious variants detected in fetuses with structural abnormalities (Xu et al., 2023). The condition of mosaicism is frequently overlooked because of this high percentage. However, approximately 3.4% of clinically apparent de novo cases were not indeed de novo. Instead, they were low‐level gonosomal mosaicism inherited from their progenitors (Zemet et al., 2022). In the clinical setting, no guidelines exist for diagnosing and quantifying mosaicism in a high‐risk family with an affected child (Zemet et al., 2022). Moreover, the methodologies used to detect mosaicism are fraught with technological challenges (Ha et al., 2023). Therefore, despite its significant difference in recurrence risk, the definitive diagnosis of genetic conditions with unaffected parents in clinical practice is always between de novo and mosaicism, although they are sometimes overlapping complex to determine (Kadlubowska & Schrauwen, 2022).

Rett syndrome (RTT) is an X‐linked dominant genetic disorder affecting neurodevelopment, with a prevalence of approximately 1/14,000 live female births (Petriti et al., 2023). Although numerous reports showed that the causal MECP2 mutations resulted in the classical RTT cases (90%–95%) (Lu et al., 2022) (OMIM #312750), CDKL5 and FOXG1 variants were discovered causal for atypical RTT of early seizure variant and congenital variant (OMIM #613454), respectively (Zhang et al., 2019). Most RTT patients are spontaneous, and the etiology is described with over 99% due to de novo variants (DNVs) in the MECP2 gene (Trappe et al., 2001). In rare cases, RTT can pass from an affected maternal X chromosome to a male and cause illness. Besides compelling evidence linking DNVs to the condition, a few studies have shown that parental mosaicism might cause RTT in patients, leading to a significant higher recurrence rate among family members (McMahon et al., 2015; Venâncio et al., 2007; Zhang et al., 2019).

Tubulinopathy is a neurodevelopmental disorder caused by autosomal dominant mutations in genes encoding tubulin subunits such as TUBA1A (OMIM #611603), TUBB2B (OMIM #610031), TUBB3 (OMIM #614039), TUBB2A (OMIM #615763), TUBB (OMIM #615771), and TUBG1 (OMIM #615412). It has a broad spectrum of clinical manifestations, most characteristic of non‐progressive complex brain malformations (Torella et al., 2023). Similar to RTT, over 95% of Tubulinopathy patients are diagnosed with de novo pathogenic variants (Bahi‐Buisson & Maillard, 2016 [Updated 2021 Sep 16]) and the inherited condition correlated to TUBB2B and TUBB3 pathogenic variants rather than others (Bahi‐Buisson & Maillard, 2016 [Updated 2021 Sep 16]). Some explanations for de novo determination were the under‐recognition of family history or the incomplete penetrance. Although mosaicism was rarely mentioned in Tubulinopathy, some studies showed that parental mosaicism might cause this condition and lead to a series of affected family members (Jamuar & Walsh, 2014; Oegema et al., 2015; Zillhardt et al., 2016).

In terms of recurrent risk, DNVs and mosaicism were remarkably of different magnitudes, reliant on case‐by‐case evaluations. DNV was a rare event that contributed to approximately 1% de novo recurrence among offspring (Bernkopf et al., 2023); however, the recurrence rate could rise to 50% if the apparent de novo mutation was truly inherited from parental mosaicism. One study showed that the detection of at least 1% of affected cells existing in parental blood could lead to a 24% recurrence risk, and it was up to 50% if mosaic cells in parental blood samples were greater than 6% (Rahbari et al., 2016). Therefore, in a clinical decision, directing the diagnosis to the de novo or mosaic cause is essential in anticipating familial recurrence and proposing a strategic pregnancy plan for affected families. The process is not without genetic counseling to mitigate the risk in their children, an important part of informing the families of current fetus/child conditions and their future offspring and preparing them psychologically as well as pre‐pregnant plans for their subsequent pregnancy.

This paper provides a detailed account of two Vietnamese families with multiple children with RTT and Tubulinopathy, including experience in diagnosis, timely patient communication, and further discussions on the clinical workup for managing recurrence in a high‐risk family in Vietnam.

2. METHODS

2.1. Data collection

The two identified families' clinical characteristics and genetic tests were obtained from medical reports.

The next‐generation sequencing (NGS) method (NextSeq, Illumina, USA) was applied with coverage of 100X for genetic sequencing. GenBank reference sequence used NM_005249.5 for gene FOXG11 and NM_006009.4 for gene TUBA1A. All identified variants in this study were evaluated and reported according to the American College of Medical Genetics and Genomics (ACMG).

3. CLINICAL CASE PRESENTATION

3.1. Familial case 1: FOXG1‐related syndrome (atypical Rett syndrome)

A pedigree of the first family is shown in Figure 1, with a 32‐year‐old mother and a 30‐year‐old father having two offspring, both genetically confirmed FOXG1‐related syndrome.

FIGURE 1.

FIGURE 1

Open in a new tab

Family pedigree with affected offspring of FOXG1‐related syndrome.

Their first daughter is now 3 years old. During pregnancy, a non‐invasive prenatal screening test (NIPT) was done with a low risk for aneuploidy and chromosome numerical disorders. At 38 weeks of gestation, the fetus was found with abnormal heart rate detected by ultrasound (US) (undetected fetal heart rate), while Doppler US showed without abnormal findings (normal blood flow recognition). Therefore, cesarean delivery was indicated, and the infant was born with suspected signs of starvation of oxygen and brain damage. At 7 months of age, the baby was shown to have an abnormal brain structure by computed tomography (CT) scan and psychomotor retardation without a family history of related conditions. At 2 years old, the clinical exome sequencing of 4503 genes was performed on her blood to diagnose the most common genetic disorders in children. Results showed that the daughter carries a variant of FOXG1 c.460dup (p.Glu154GlyfsTer301) with frameshifts. According to ACMG, it is defined as a pathogenic variant related to congenital X‐linked Rett syndrome. Sanger sequencing confirmed the variant. No copy number variants (CNVs), micro‐deletions, or duplications were found.

The parents underwent genetic testing to determine the variant origin. Their blood samples showed no variant in the FOXG1 gene using Sanger tests, directing the suspicion to DNV in a new generation. The parents were informed about the possibility of having a subsequent pregnancy with this condition, but no particular risk was determined.

Subsequently, in their next pregnancy, the US images showed no anomaly; however, the couple was encouraged to have a prenatal genetic diagnosis for their fetus. At 18 weeks of gestation, an invasive diagnosis test with an amniocentesis sample and genetic sequencing using a panel of 4503 commonly suspected genes was done. The results showed that the fetus carries a variant of the FOXG1 gene (c.460dup (p.Glu154GlyfsTer301)), the same variant found in their older daughter, confirmed by Sanger sequencing. No CNVs, micro‐deletions, or duplications were found. The US images in the second trimester at gestational week 21 revealed that fetal biometry was between the 10th and 40th percentiles for that gestational age, and thick echogenic nodules were discovered in the right and left ventricles.

Multidisciplinary specialists counseled the parents in obstetrics, fetal medicine, pediatrics, and genetics about fetal conditions. The family was considering termination of pregnancy after fully understanding the fetal risk.

While both affected daughters carry the same pathogenic variant of FOXG1 related to congenital Rett syndrome, evidence of unseen causal mutations in parental blood samples had suggested the condition of parental mosaicism (germline or gonosomal) with a significant higher chance of recurrence compared to de novo mutations. After all, the couple has a consultation about the risk of having a recurrent baby, which is up to 50%, and the prenatal diagnosis or preimplantation genetic testing for monogenic disease (PGT‐M) for the next pregnancy is essential and needs to be prioritized.

3.2. Familial case 2: TUBA1A‐associated Tubulinopathy

A pedigree of the second family is shown in Figure 2. The unrelated parents (31‐year‐old mother and 37‐year‐old father) had two affected fetuses with TUBA1A‐associated Tubulinopathy, while their oldest son was asymptomatic with this disorder.

FIGURE 2.

FIGURE 2

Open in a new tab

Family pedigree with affected offspring of TUBA1A‐associated Tubulinopathy.

A woman went to the hospital for a pregnancy check‐up at 23 weeks of gestation. In the second trimester, images of the US showed abnormal fetal brain structures, describing midline distortion, dysmorphia of both lateral ventricles frontal horns (squared shape), underdeveloped and asymmetric sylvian fissure, and vermian hypoplasia, all suggesting Tubulinopathy. In the first trimester, this pregnancy was confirmed with neither risk for aneuploidy nor other chromosome numerical disorders by NIPT and without a family history of the related condition. Family history showed their first offspring, a 4‐year‐old son, had significant clinical symptoms of deficits in speech and language functions without cause confirmed.

The parents were consulted about the possibility of Tubulinopathy in their fetus and decided to undertake immediate genetic diagnosis by invasive amniocentesis followed by whole‐exome sequencing (WES). Even though the WES found an uncertain missense variant of TUBA1A c.172G>A (p.Ala58Thr) according to ACMG, the phenotype of lissencephaly by this variant and clinical suspicion was in line with the severe condition of Tubulinopathy. No CNVs, micro‐deletions, or duplications were found. The parents decided to terminate the pregnancy due to the severe fetal condition. Sanger sequencing was offered to determine whether the parents passed on the variant to their offspring. Surprisingly, neither parent had a variant of TUBA1A. Therefore, the physician considered the condition most likely suggested de novo mutation of TUBA1A. No information regarding genetic counseling for the family was recorded.

Seven months later, the mother was pregnant with her third offspring. It seemed to be in the same situation as the previous pregnancy. This pregnancy had no abnormal findings within its first trimester. However, at 21 weeks of gestation, the family was informed about the possibility of lissencephaly related to Tubulinopathy by the US. The images showed underdevelopment sulcation, dysplasia of corpus callosum, abnormalities of the anterior complexes, ectopic gray matter along the ventricular wall, increased size of bilateral lymph nodes, small and flattening of pons, and vermian hypoplasia. The MRI images confirmed the US findings, and the parents agreed to further genetic testing. An amniocentesis sample was analyzed using WES and CNV sequencing (CNVseq). Results showed TUBA1A c.172G>A (p.Ala58Thr) in the current fetus, matching the variant found in the previously affected fetus. Only after the third offspring was confirmed with TUBA1A mutations was the oldest son processed for genetic testing, and the results showed no variant of TUBA1A, which was consistent with his clinical features of no phenotype of Tubulinopathy.

The couple was offered genetic counseling about their familial condition, Tubulinopathy. Overall, the physician suggested a clinical diagnosis of parental mosaicism of TUBA1A‐associated Tubulinopathy, which led to the shared mutation in two siblings. They were informed about the high risk of recurrence and the need to prepare and carefully manage their ongoing pregnancy.

4. DISCUSSION

Based on the characteristics of unaffected parents having offspring with shared variants, both families were determined to have a likelihood of parental mosaicism (germline or gonosomal mosaicism) rather than the offspring containing de novo variants, notwithstanding the extremely high contribution of DNVs (95%–99%) in these two genetic disorders.

4.1. Atypical RTT

In the first family with atypical RTT, the two siblings of a healthy couple were determined to carry FOXG1 c.460dup (p.Glu154GlyfsTer301). Apparently, no significant clinical signs were recorded within the gestation of both probands, especially in their first trimester. The diverse clinical manifestations of RTT could explain this. Accordingly, almost all RTT patients have symptoms from 6‐ to 8‐month‐old; only the case harboring FOXG1 variant would have an earlier onset in infancy (before 6 months) (Lu et al., 2022). In this reported family, the older sister was 7 months old, when with psychomotor retardation and damaged brain images visualized on a CT scan; she underwent genetic testing at 2 years old. In the second offspring, the US suggested abnormality at 21 weeks of gestation, after the FOXG1 mutation was identified. Thanks to the older sister being confirmed with the mutation, an invasive diagnostic test was performed on the second fetus at 18 weeks, regardless of no clinical appearance at the time of testing. As seen from this family's experience, clinical features might not be good indicators for early‐stage RTT diagnosis, especially in the prenatal period, which always leads to the RTT's severity at the time of detectable signs and symptoms.

In 2005, a report about RTT consecutively happening in family siblings confirmed that germline mosaicism was possibly causing this condition. The authors recommended proposing prenatal diagnosis to all couples with an RTT daughter, even if the de novo mutation was apparently confirmed (Mari et al., 2005). The study highlighted the importance of proactive prenatal diagnosis for a pregnancy with a family history of an RTT daughter, which was performed in our case. A 2015 study was the first to report on FOXG1‐related disorders with the origin of parental mosaicism (McMahon et al., 2015). It showed a cohort of three families with each of the familial siblings sharing the same FOXG1 mutation (c.572T>G, c.515_577del63, or c.460dupG). Interestingly, one of those variants was again reported in our study case (FOXG1 c.460dupG). Among these three families, only one had parental DNA analyzed on blood, skin, and saliva samples, which revealed maternal DNA harboring the same FOXG1 mutation as their offspring. The other two families could not be tested with parents' multiple tissues. In line with our case, only parental blood samples were assessed; however, the notable point of a variant shared by siblings strongly suggested parental mosaicism of origin rather than de novo. The family had genetic counseling for every RTT confirmation. Nevertheless, only after the second pregnancy was diagnosed were they sufficiently informed about the high suspicion of parental mosaicism and significantly high risk of recurrence (50%), encouraging the PGT‐M preparation for future pregnancy if possible. This case report is helpful because RTT had a much lower diagnosis rate with FOXG1 compared to MECP2, and there was still a gap in evidence regarding FOXG1 mutations in RTT disorder. This study would add to the current global data of FOXG1 in developing RTT, especially its origination from parental mosaicism.

4.2. Tubulinopathy

In the second family with Tubulinopathy, TUBA1A c.172G>A (p.Ala58Thr) was determined as a pathogenic variant regardless of its novel report. Even though the first offspring was confirmed with Tubulinopathy both clinically and genetically, the parents were not well prepared to prevent recurrence in the next pregnancy. Not until the prenatal US showed abnormalities of lissencephaly related to Tubulinopathy at 21 gestational weeks, did the mother undergo genetic testing for her fetus, and recurrence was confirmed. Based on existing evidence, even though the pathogenic variant could not be detected in parental leukocyte DNA, Tubulinopathy caused by parental mosaicism should always be discussed in genetic consulting because it has a greater recurrent risk compared to the general population (Bahi‐Buisson & Maillard, 2016 [Updated 2021 Sep 16]). Also, prenatal testing and/or PGT in identified families with affected children should be encouraged, but much based on personal familial decisions and discussions (Bahi‐Buisson & Maillard, 2016 [Updated 2021 Sep 16]).

It is an intricate process to identify and differentiate mosaicism from DNVs, especially in clinical workup. De novo is defined as a variant that primarily occurs in the first generation when none of the precursors are detected with clinical features and/or causal mutation related to the investigated condition. The true DNVs can be classified based on the timing of their occurrence (prezygotic, conception in the zygote, or postzygotic derivation) (Zemet et al., 2022) and can used to explain the diverse mosaic levels in progenitors. Advanced paternal age was one of the main factors in increasing DNV risk, and approximately 80% of de novo germline variants were shown to originate from the paternal allele (Kong et al., 2012; Zemet et al., 2022).

In mosaicism, the number of affected cells and cell lineages as well as single or multiple tissues/organs is dependent much on the timing of variant derivation, which leads to the distinction of variant allele frequency (VAF) and diversity of representative tissues that harbor the deleterious variants (Kim et al., 2023). A low variant level is worth mentioning as the great barrier leading to a low measurable chance of mosaicism. While a mosaic condition could cause a low VAF level (even reported very low <1%) (Gambin et al., 2020), methods using Sanger sequencing and standard WES with variant‐calling pipelines were limited when VAFs were lower than 10% (Kadlubowska & Schrauwen, 2022; Zemet et al., 2022). Additionally, blood sample analysis is not always effective and can lead to underestimate the condition, especially when there is a suspicion of paternal gonadal mosaicism (Breuss et al., 2020). Incidentally, the use of control and reference standards for detection accuracy in mosaic variant analysis should also be considered in the sequencing process (Ha et al., 2022). On the whole, clinically determining the mosaicism is a significant challenge, always requires more advanced and deep sequencing methods, combined with sensitive techniques (amplicon‐based NGS, ddPCR, and blocker displacement amplification), and is highly encouraged with multiple sites and tissues assessed.

Even when the separation of de novo and parental mosaics is conducted, the recurrence risk is also stratified by groups of mosaics. The parental gonosomal condition had the highest risk of recurrence, followed by parental germline (low to intermediate risk). Fortunately, postzygotic mosaicism seems to have a similar risk within the general population (Zemet et al., 2022). There were models designed to predict the recurrence risk in DNVs, in which the mosaicism could not be excluded. Among those, “variant shared by siblings” was the major element used to highlight the recurrence risk. With a larger number of siblings shared, the recurrence was always at a higher rate (Zemet et al., 2022). Additionally, the younger paternal age of these affected families could help conclude with a higher risk of recurrence. In other words, the recurrent risk would decrease by 2.3% per year with the paternal age increase (Zemet et al., 2022) due to the true DNVs associated with advanced father's age rather than parental mosaic condition.

These two families had suspected parental mosaic conditions. Nevertheless, the confirmations for the parental inheritance by germline cells were not sufficiently assessed. Generally, the limitation of both case reports was that only blood leukocytes were used to assess parental DNA, while other samples recommended for confirming mosaic conditions such as skin, hair follicles, saliva, semen, buccal swabs, and urine were not processed (Zhang et al., 2019). Moreover, Sanger sequencing was used to detect the parental variants in this study, and it limited the accuracy in detecting variants with low VAF, as mentioned. Those factors can lead to underestimate parental mosaicism in real‐world settings. Overall, only based on clinical characteristics and physician experience, the clinical diagnoses were directed to parental mosaic, and families were supported with genetic counseling. The experience from these cases can assist physicians in managing and offering timely and sufficient genetic consulting to their future patients.

In conclusion, the clinical distinction between DNVs and mosaics is not always optimized and includes challenges because of the complexity of advanced techniques/processes involved. Instead, noticing the risk of mosaicism, carefully consulting the family with an affected child, and proactively managing high‐risk families would bring more benefits for their future pregnancies.

AUTHOR CONTRIBUTIONS

All authors contributed to the study's conception and design. Hai Xuan Tang and Y‐Thanh Lu drafted the manuscript. Hung Sang Tang supervised the work and finalized the manuscript. All authors commented on the submitted versions of the manuscript and have read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no potential conflicts of interest.

ETHICAL COMPLIANCE

The Hospital Ethics Committees approved the study. Parents provided informed consent for the use of clinical and genetic information of their family members with anonymization for research purposes.

PATIENT CONSENT STATEMENT

The families gave informed written consent regarding using their clinical and genetic data with anonymization.

ACKNOWLEDGMENTS

We thank all patients who participated in this study and gave consent to report findings in this paper. We thank A Jansen of Angela Jansen & Associates, for her editorial services in preparing the manuscript for publication.

Tang, H. X. , Lu, Y.‐T. , Ha, T. M. T. , Tran, N.‐T. , Dang, D. M. , Ly, S. X. , Bui, T. H. T. , Vo, S. T. , Thai, M. D. , Nguyen, V. D. , Nguyen, T. V. , Dinh, L. T. , Luong, L.‐A. , Doan, K.‐P. , Nguyen, K. H. T. , Do, T.‐T. , Truong, D.‐K. , Giang, H. , Nguyen, H.‐N. , … Tang, H. S. (2024). Parental mosaicism rather than de novo variants in FOXG1 ‐related syndrome and TUBA1A ‐associated Tubulinopathy: Familial case reports. Molecular Genetics & Genomic Medicine, 12, e2484. 10.1002/mgg3.2484

Hai Xuan Tang and Y‐Thanh Lu have equal contributions.

Contributor Information

Thu Huong Nhut Trinh, Email: drnhuthuong@gmail.com.

Hung Sang Tang, Email: sangtang@genesolutions.vn.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

REFERENCES

  1. Bahi‐Buisson, N. , & Maillard, C. (2016. [Updated 2021 Sep 16]). Tubulinopathies Overview. GeneReviews® [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK350554/
  2. Bernkopf, M. , Abdullah, U. B. , Bush, S. J. , Wood, K. A. , Ghaffari, S. , Giannoulatou, E. , Koelling, N. , Maher, G. J. , Thibaut, L. M. , Williams, J. , Blair, E. M. , Kelly, F. B. , Bloss, A. , Burkitt‐Wright, E. , Canham, N. , Deng, A. T. , Dixit, A. , Eason, J. , Elmslie, F. , … Goriely, A. (2023, February 15). Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation. Nature Communications, 14(1), 853. 10.1038/s41467-023-36606-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Breuss, M. W. , Antaki, D. , George, R. D. , Kleiber, M. , James, K. N. , Ball, L. L. , Hong, O. , Mitra, I. , Yang, X. , Wirth, S. A. , Gu, J. , Garcia, C. A. B. , Gujral, M. , Brandler, W. M. , Musaev, D. , Nguyen, A. , McEvoy‐Venneri, J. , Knox, R. , Sticca, E. , … Gleeson, J. G. (2020, January 1). Autism risk in offspring can be assessed through quantification of male sperm mosaicism. Nature Medicine, 26(1), 143–150. 10.1038/s41591-019-0711-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Gambin, T. , Liu, Q. , Karolak, J. A. , Grochowski, C. M. , Xie, N. G. , Wu, L. R. , Yan, Y. H. , Cao, Y. , Coban Akdemir, Z. H. , Wilson, T. A. , Jhangiani, S. N. , Chen, E. , Eng, C. M. , Muzny, D. , Posey, J. E. , Yang, Y. , Zhang, D. Y. , Shaw, C. , Liu, P. , … Stankiewicz, P. (2020, November). Low‐level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected mendelian conditions. Genetics in Medicine, 22(11), 1768–1776. 10.1038/s41436-020-0897-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ha, Y.‐J. , Kang, S. , Kim, J. , Kim, J. , Jo, S.‐Y. , & Kim, S. (2023, October 12). Comprehensive benchmarking and guidelines of mosaic variant calling strategies. Nature Methods, 20, 2058–2067. 10.1038/s41592-023-02043-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ha, Y.‐J. , Oh, M. J. , Kim, J. , Kim, J. , Kang, S. , Minna, J. D. , Kim, H. S. , & Kim, S. (2022, February 3). Establishment of reference standards for multifaceted mosaic variant analysis. Scientific Data, 9(1), 35. 10.1038/s41597-022-01133-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Jamuar, S. S. , & Walsh, C. A. (2014, November 20). Somatic mutations in cerebral cortical malformations. The New England Journal of Medicine, 371(21), 2038. 10.1056/NEJMc1411784 [DOI] [PubMed] [Google Scholar]
  8. Kadlubowska, M. K. , & Schrauwen, I. (2022, February 11). Methods to improve molecular diagnosis in genomic cold cases in pediatric neurology. Genes (Basel), 13(2), 333. 10.3390/genes13020333 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kim, S. H. , Kwon, S. S. , Park, M. R. , Lee, H. A. , Kim, J. H. , Cha, J. , Kim, S. , Baek, S. T. , Kim, S. H. , Lee, J. S. , Kim, H. D. , Choi, J. R. , Lee, S. T. , & Kang, H. C. (2023, August). Detecting low‐variant allele frequency mosaic pathogenic variants of NF1, TSC2, and AKT3 genes from blood in patients with neurodevelopmental disorders. The Journal of Molecular Diagnostics, 25(8), 583–591. 10.1016/j.jmoldx.2023.04.003 [DOI] [PubMed] [Google Scholar]
  10. Kong, A. , Frigge, M. L. , Masson, G. , Besenbacher, S. , Sulem, P. , Magnusson, G. , Gudjonsson, S. A. , Sigurdsson, A. , Jonasdottir, A. , Jonasdottir, A. , Wong, W. S. W. , Sigurdsson, G. , Walters, G. B. , Steinberg, S. , Helgason, H. , Thorleifsson, G. , Gudbjartsson, D. F. , Helgason, A. , Magnusson, O. T. , … Stefansson, K. (2012, August 1). Rate of de novo mutations and the importance of father's age to disease risk. Nature, 488(7412), 471–475. 10.1038/nature11396 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lu, G. , Zhang, Y. , Xia, H. , He, X. , Xu, P. , Wu, L. , Li, D. , Ma, L. , Wu, J. , & Peng, Q. (2022). Identification of a de novo mutation of the FOXG1 gene and comprehensive analysis for molecular factors in Chinese FOXG1‐related encephalopathies. Frontiers in Molecular Neuroscience, 15, 1039990. 10.3389/fnmol.2022.1039990 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mari, F. , Caselli, R. , Russo, S. , Cogliati, F. , Ariani, F. , Longo, I. , Bruttini, M. , Meloni, I. , Pescucci, C. , Schurfeld, K. , Toti, P. , Tassini, M. , Larizza, L. , Hayek, G. , Zappella, M. , & Renieri, A. (2005, March). Germline mosaicism in Rett syndrome identified by prenatal diagnosis. Clinical Genetics, 67(3), 258–260. 10.1111/j.1399-0004.2005.00397.x [DOI] [PubMed] [Google Scholar]
  13. McMahon, K. Q. , Papandreou, A. , Ma, M. , Barry, B. J. , Mirzaa, G. M. , Dobyns, W. B. , Scott, R. H. , Trump, N. , Kurian, M. A. , & Paciorkowski, A. R. (2015, December). Familial recurrences of FOXG1‐related disorder: Evidence for mosaicism. American Journal of Medical Genetics. Part A, 167a(12), 3096–3102. 10.1002/ajmg.a.37353 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Oegema, R. , Cushion, T. D. , Phelps, I. G. , Chung, S. K. , Dempsey, J. C. , Collins, S. , Mullins, J. G. , Dudding, T. , Gill, H. , Green, A. J. , Dobyns, W. B. , Ishak, G. E. , Rees, M. I. , & Doherty, D. (2015, September 15). Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes. Human Molecular Genetics, 24(18), 5313–5325. 10.1093/hmg/ddv250 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Petriti, U. , Dudman, D. C. , Scosyrev, E. , & Lopez‐Leon, S. (2023, January 16). Global prevalence of Rett syndrome: Systematic review and meta‐analysis. Systematic Reviews, 12(1), 5. 10.1186/s13643-023-02169-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Rahbari, R. , Wuster, A. , Lindsay, S. J. , Hardwick, R. J. , Alexandrov, L. B. , Al Turki, S. , Dominiczak, A. , Morris, A. , Porteous, D. , Smith, B. , Stratton, M. R. , Hurles, M. E. , & UK10K Consortium . (2016, February 1). Timing, rates and spectra of human germline mutation. Nature Genetics, 48(2), 126–133. 10.1038/ng.3469 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Torella, A. , Ricca, I. , Piluso, G. , Galatolo, D. , De Michele, G. , Zanobio, M. , Trovato, R. , De Michele, G. , Zeuli, R. , Pane, C. , Cocozza, S. , Saccà, F. , Santorelli, F. M. , Nigro, V. , & Filla, A. (2023, October 1). A new genetic cause of spastic ataxia: The p.Glu415Lys variant in TUBA4A. Journal of Neurology, 270(10), 5057–5063. 10.1007/s00415-023-11816-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Trappe, R. , Laccone, F. , Cobilanschi, J. , Meins, M. , Huppke, P. , Hanefeld, F. , & Engel, W. (2001, May). MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. American Journal of Human Genetics, 68(5), 1093–1101. 10.1086/320109 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Venâncio, M. , Santos, M. , Pereira, S. A. , Maciel, P. , & Saraiva, J. M. (2007, August 1). An explanation for another familial case of Rett syndrome: Maternal germline mosaicism. European Journal of Human Genetics, 15(8), 902–904. 10.1038/sj.ejhg.5201835 [DOI] [PubMed] [Google Scholar]
  20. Xu, N. , Shi, W. , Cao, X. , Zhou, X. , Jin, L. , Huang, H. F. , Chen, S. , & Xu, C. (2023, September). Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations. Journal of Medical Genetics, 60(9), 910–917. 10.1136/jmg-2022-108920 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Zemet, R. , Van den Veyver, I. B. , & Stankiewicz, P. (2022, June). Parental mosaicism for apparent de novo genetic variants: Scope, detection, and counseling challenges. Prenatal Diagnosis, 42(7), 811–821. 10.1002/pd.6144 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Zhang, Q. , Yang, X. , Wang, J. , Li, J. , Wu, Q. , Wen, Y. , Zhao, Y. , Zhang, X. , Yao, H. , Wu, X. , Yu, S. , Wei, L. , & Bao, X. (2019, June). Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort. Genetics in Medicine, 21(6), 1330–1338. 10.1038/s41436-018-0348-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Zillhardt, J. L. , Poirier, K. , Broix, L. , Lebrun, N. , Elmorjani, A. , Martinovic, J. , Saillour, Y. , Muraca, G. , Nectoux, J. , Bessieres, B. , Fallet‐Bianco, C. , Lyonnet, S. , Dulac, O. , Odent, S. , Rejeb, I. , Jemaa, L. B. , Rivier, F. , Pinson, L. , Geneviève, D. , … Chelly, J. (2016, April 1). Mosaic parental germline mutations causing recurrent forms of malformations of cortical development. European Journal of Human Genetics, 24(4), 611–614. 10.1038/ejhg.2015.192 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Articles from Molecular Genetics & Genomic Medicine are provided here courtesy of Blackwell Publishing

RESOURCES