Coexistence of Fragile-X Syndrome,8p23.1 Deletion,and Balanced Translocation t(7;10)(p10;q24) in a Single Family

Abstract

Aims:

Fragile-X syndrome (FXS) is the most common inherited form of intellectual disability; it is caused by an abnormal CGG-repeat expansion at the FMR1 gene. However, a few cases of girls with mutations in the FMR1 gene have been reported in the literature. In this study, we describe the clinical and genetic assessment of a family who exhibits the unusual coexistence of FXS, an 8p23.1 deletion, and balanced translocation t(7;10)(p10;q24) in multiple members, including a symptomatic girl with FXS.

Materials and Methods:

All of the family members underwent comprehensive clinical and neurological examinations. All members of the family were also molecularly diagnosed using a combination of fluorescent-polymerase chain reaction (PCR), Triplet Repeat Primed-PCR, capillary electrophoresis, and karyotyping.

Results:

We identified a male proband and a female patient that presented with the craniofacial characteristics of FXS, neuropsychomotor developmental delay, speech delay, intellectual deficit, and a positive molecular diagnosis of FXS. Interestingly, the female patient presented with a severe phenotype also associated with the presence of 8p23.1 deletion, while the proband patient presented a balanced translocation t(7;10)(p10;q24). Moreover, we detected multiple carriers of the FXS premutation in the family.

Conclusions:

To our knowledge, we describe for the first time the simultaneous occurrence of FXS and an 8p23.1 deletion and their possible synergistic effects on the phenotype of a female patient. Moreover, we describe the coexistence of FXS, an 8p23.1 deletion, and a balanced translocation t(7;10)(p10;q24) in the same family.

Introduction

Fragile-X syndrome (FXS) is a frequent genetic cause of intellectual disability worldwide (Bagni et al., 2012). FXS is caused by an abnormal expansion of CGG repeats (>200) in exon 1 of the FMR1 gene, which leads to a decrease of the FMRP protein, producing changes in neuronal dendrites and synaptic dysfunction (Bagni et al., 2012). FXS is characterized by severe intellectual disability, arched palate, midface hypoplasia, and large cupped ears in male patients (Hagerman et al., 2017). Moreover, it may present with autistic disorder (about 60%) (Schaefer and Mendelsohn, 2008) and epilepsy (10-20%) (Heard et al., 2014), whereas females present only mild intellectual disturbances (Hagerman et al., 2017).

The present study reports the case of a complex family with FXS associated with 8p23.1 deletion and balanced translocation (7;10) in different members. Therefore, we performed a comprehensive clinical, neurological, and molecular characterization of this family.

Materials and Methods

Patients and outcome analysis

A Mexican family with a history of intellectual disability that included patients and asymptomatic relatives (Fig. 1A) was recruited by the National Rehabilitation Institute-Luis Guillermo Ibarra Ibarra (INR-LGII, Mexico City). The protocol was approved by the Ethics-Research Committee of the INR-LGII (protocol: 45/13), and informed consent was obtained from all the participants. All evaluations were performed according to the Helsinki Declaration. The neurological assessment and genetic tests are described in Supplementary Data, in Supplementary Appendices SA1 and SA2, respectively (Ostrosky et al., 2012; Flores et al., 2012).

FIG. 1.

Pedigree of Mexican kindreds with FXS and molecular diagnosis. (A) Pedigree of the FXS proband's family. The numbers below symbols indicate first the current age of individuals, second the number of repeats at FMR1 locus, and finally, the cytogenetic findings. X and Y represent X and Y chromosomes, respectively. The filled symbols indicate clinically affected individuals, symbols with a central point mark indicate asymptomatic carriers, and the symbol with the upper right quadrant indicates an intellectual disability of unknown cause (molecular diagnosis was not performed). (B-E) Molecular and cytogenetic analysis of II.2, II.3, III.8, and III.9 individuals, respectively. In the upper panels, the genotyping of CGG repeats at the FMR1 gene by fluorescent PCR and TP-PCR is depicted; the lower panels depict the cytogenetic findings. FXS, fragile-X Syndrome; TP-PCR, triplet repeat primed-PCR.

Results

Mexican kindred

In this work, we report a family with compatible FXS characteristics. However, we detected unusual clinical features; hence we performed an exhaustive clinical and genetic analysis.

Initially, we described an 18-year-old male index patient (III.8; Fig. 1A), the third child born to a healthy nonconsanguineous couple (II.2 and II.3; Fig. 1B, C), who scored 20-points on the Hagerman checklist and had an intellectual coefficient (IQ) of 55 on the Terman-Merrill scale. The pregnancy was uneventful, and the patient was born at 39 gestational weeks. From childhood, the parents noted a severe delay in language, perceptual-motor difficulties, and short attention spans. Today, the patient showed clinical features that included arched palate, large cupped ears, prominent forehead, hyperextensible small joints (5-points on the Beighton scale), general hypotonia, delay in neuropsychomotor development, speech delay, and intellectual deficit.

Interestingly, family history (Fig. 1A) revealed a younger sister with similar clinical manifestations (III.9) and two healthy sisters (III.6 and III.7). The patient III.9 scored 19 on the Hagerman checklist and 47 on the Terman-Merrill scale; however, she presented a lower degree of joint hypermobility (2-points on the Beighton scale), an integral spine, and she was friendly and cooperative. Curiously, she exhibited anxiety and autism spectrum disorder, and an echocardiogram revealed congenital heart defects (interatrial communication). Finally, the pedigree showed two cousins of the proband with clinical features compatible with FXS (III.4 and III.5).

Neurological analysis

All family members exhibited extremely low or borderline scores on the Wechsler Adult Intelligence Scale-III (WAIS-III), except the father, who obtained a low average score (Table 1). In this regard, the patient III.8 presented moderate intellectual disability with alterations of language related to reading and writing deficiency. Furthermore, he exhibited damaged executive functions. Similarly, patient III.9 exhibited severe impairment in all areas of development, fulfilling the diagnostic criteria for severe intellectual disability. She presented a substantial deficit in language comprehension, echolalia, and difficulty in speech articulation. She also exhibited signs of cognitive fatigue, echopraxia, delay in psychomotor development, and a deficit of perceptual processes. The father (II.2) exhibited mild alterations in working memory and executive functions. Likewise, the mother (II.3) demonstrated slight impairment in risk/benefit processing. Similarly, healthy sisters (III.6 and III.7) had low performance in attentional-working memory processes; in particular, III.7 exhibited more impairment of executive functions, whereas III.6 presented some learning problems.

Table 1.

Analysis of Neurological Assessment

Cases	WAIS III						Neuropsi			NEBEF attention and memory
Cases	FSIQ	Range	VIQ	Range	PIQ	Range	Total	Range	Subscales deficit in attention	Prefrontal cortex dorsolateral	Range	Prefrontal cortex orbitomedial	Range
II.6	84	Low average	83	Low average	93	Low average	97	Normal	0	78	Mild alteration	96	Normal
II.7	77	Borderline	78	Borderline	85	Low average	96	Normal	0	99	Normal	76	Mild alteration
III.3	75	Borderline	79	Borderline	82	Low average	85	Normal	3	69	Severe alteration	94	Normal
III.4	74	Borderline	79	Borderline	81	Low average	65	Severe alteration	3	116	Normal	102	Normal
III.5	<60	Extremely low	66	Extremely low	60	Extremely low	—	—	—	—	—	—	—
III.6	—	N/A	—	N/A	—	N/A	—	—	—	—	—	—	—

Wechsler Adult Intelligence Scale-III (WAIS-III).

FSIQ, full scale intelligence quotient; NEBEF, neuropsychological battery of executive functions and frontal lobes; PIQ, performance intelligence quotient; VIQ, verbal intelligence quotient.

The magnetic resonance study of III.8 (Supplementary Fig. S1A) revealed a slight symmetrical reduction in brain volume. The study of III.9 did not reveal identifiable structural alterations (Supplementary Fig. S1B). The electroencephalographic study showed data of diffuse and generalized cortico-subcortical abnormalities in both patients (data not shown). We observed epileptiform graphoelements, characterized by the presence of acute waves and generalized slow waves of bilateral frontal predominance. The epileptiform activity was more frequent in the patient III.9.

Genetic characterization

A molecular test was performed to the patient III.8, indicating a positive result for FXS (Fig. 1D). Subsequently, the whole family was studied (Fig. 1A). The father (II.2; Fig. 1B) and a daughter (III.6) were negative for the FXS mutation, whereas the mother (II.3; Fig. 1C) and one daughter (III.7) were carriers of a premutation allele (118 and 114 CGG repeats, respectively). Interestingly, the female patient III.9 exhibited a full mutation (Fig. 1E). Finally, one sister of patient II.3 presented a premutation allele (113 CGG repeats) (II.1); subsequently, we analyzed her offspring and found two healthy individuals (III.2 and III.3) and two patients aged 16 and 13 years with 860 CGG repeats approximately (III.4 and III.5) (Fig. 1A). These patients scored 18 and 19 on the Hagerman checklist, respectively. Karyotyping was performed in all members of the nuclear family (Fig. 1B-E). Patients III.8 and III.9 presented an X fragile site. Unexpectedly, karyotyping detected a balanced translocation t(7;10)(p10;q24) in the proband (III.8), in his father (II.2), and his healthy sister (III.6), whereas his affected sister (III.9) showed an 8p23.1 deletion (Fig. 1). None of the second-grade relatives showed any cytogenetic alteration (II.1, III.4, and III.5).

Discussion

Initially, the clinical characteristics of the family case clearly indicated the presence of FXS. However, symptomatic female patients are very infrequent. Moreover, we identified unusual features in the patient (III.9), which led to the identification of a synergistic effect. Interestingly, we found the simultaneous occurrence of FXS and an 8p23.1 deletion in the female patient.

8p23.1 deletion is considered a rare mutation (Gümüşlü et al., 2015; Khelifa et al., 2015), which causes intellectual disability, growth retardation, psychomotor delay, microcephaly, and congenital heart disease (Digilio et al., 2011; Gümüşlü et al., 2015; Khelifa et al., 2015). These findings depict that FXS and 8p23.1 deletion may cause similar symptomatology. In this respect, facial stigmata exhibited by the patient III.9 may be due to the FXS disease condition. However, the sloping forehead, the deep-set eyes, the high nasal bridge, and the low implant ear pavilions have also been described in patients with the 8p23.1 deletion (Ballarati et al., 2011). Noteworthy, the patient III.9 suffers a congenital cardiopathy, which is frequent in 8p23.1 deletion (Digilio et al., 2011; Longoni et al., 2012; Khelifa et al., 2015; Molck et al., 2015). Likewise, the female patient exhibited autism and anxiety, frequent disorders in FXS. Nevertheless, anxiety has not been reported in patients with 8p23.1 del (Bagni et al., 2012; Gümüşlü et al., 2015; Hagerman et al., 2017). Although the female patient presented a slight increase in intellectual disability than her brother, this effect is common in both conditions. However, it could be interesting to assess the IQ by the Wechsler Intelligence-Scale for Children to reach higher sensibility analysis. Therefore, it is feasible to speculate that both genetic abnormalities could contribute to increasing the severity of her clinical symptoms, a phenomenon described in patients with concomitant FXS and Down syndrome (Saldarriaga et al., 2017). Although it is difficult to tease out the relative contributions of different phenotypes in patients with multiple genetic disorders, physical, psychological, and occupational therapy can be modified in these patients. Moreover, clinical care focusing on cardiac support could ameliorate the effect of her disease on her daily life.

In contrast, our results showed the presence of more genetic abnormalities in all of the remaining family members. In the patient III.8, in addition to FXS, we found a balanced translocation t(7;10)(p10;q24). Moreover, this abnormality was found in his father (II.2) and his healthy sister (III.6). In the majority of individuals, these translocations may be harmless because these usually possess the genetic material necessary for healthy development (Zhang et al., 2018). However, when the cells of carriers divide to give rise to a sperm or egg for reproduction, that cell can receive extra genetic material or be devoid of it, leading to recurrent miscarriages or a child with intellectual deficit or congenital malformations (Zhang et al., 2018). Therefore, these incidental findings are significant and may have an essential benefit to the family, such as genetic counseling.

Finally, the patients II.3 and III.7 (carriers of premutation alleles) exhibited mild cognitive impairment in agreement with previous studies (Artigas-Pallares et al., 2001). However, the neuropsychological assessments revealed low scores in nearly all members, even in relatives who only present balanced translocation, which can be explained by the low socioeconomic status of the family (Flores et al., 2012; Ostrosky et al., 2012).

In summary, we describe here, to our knowledge for the first time, the simultaneous occurrence of FXS and 8p23.1 deletion in a patient. Despite the clinical diagnosis, clinicians must consider unusual features to determine a robust diagnosis that may contribute to guiding palliative treatment, which ultimately will ameliorate the effect of the disease on the patients' everyday life. Finally, genetic testing is essential to disease management and genetic counseling for the family.

Footnotes

Acknowledgment

The authors would like to thank the family described for their willingness to participate in this study.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the SECITI grant (grant number PICSA12-162) to J.J.M.

Supplementary Material

References

Artigas-Pallares

, Brun

, Gabau

(2001) Aspectos medicos y neuropsicologicos del sindrome X fragil. Rev Neurol Clin, 2:42-54.

Bagni

, Tassone

, Neri

, et al. (2012) Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest, 122:4314-4322.

Ballarati

, Cereda

, Caselli

, et al. (2011) Genotype-phenotype correlations in a new case of 8p23.1 deletion and review of the literature. Eur J Med Genet, 54:55-59.

Digilio

, Bernardini

, Lepri

, et al. (2011) Ebstein anomaly: genetic heterogeneity and association with microdeletions 1p36 and 8p23.1. Am J Med Genet Part A, 155:2196-2202.

Flores

, Ostrosky

, Lozano

(2012) Batería Neuropsicológica de Funciones Ejecutivas y Lóbulos Frontales-2, 2nd ed. Ciudad de México, México: Manual Moderno.

Gümüşlü

, Savli

, Sünnetçi

, et al. (2015) A CGH array study in nonsyndromic (Primary) autism patients: deletions on 16p13.11, 16p11.2, 1q21.1, 2q21.1q21.2, and 8p23.1. Turkish J Med Sci, 45:313-319.

Hagerman

, Berry-Kravis

, Hazlett

, et al. (2017) Fragile X syndrome. Nat Rev Dis Prim, 3:17065.

Heard

, Ramgopal

, Picker

, et al. (2014) EEG abnormalities and seizures in genetically diagnosed Fragile X syndrome. Int J Dev Neurosci, 38:155-160.

Khelifa

, Kammoun

, Hannachi

, et al. (2015) Microarray analysis of 8p23.1 deletion in new patients with atypical phenotypical traits. J Pediatr Genet, 04:187-193.

10.

Longoni

, Lage

, Russell

, et al. (2012) Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks. Am J Med Genet Part A, 158A:3148-3158.

11.

Molck

, Monteiro

, Simioni

, et al. (2015) 8p23.1 Interstitial deletion in a patient with congenital cardiopathy, neurobehavioral disorders, and minor signs suggesting 22q11.2 deletion syndrome. J Dev Behav Pediatr, 36:544-548.

12.

Ostrosky

, Gomez

, Ardila

, et al. (2012) Neuropsi Atencion y Memoria. P, 2nd ed. Ciudad de México, México: Manual. Moderno.

13.

Saldarriaga

, Ruiz

, Tassone

, et al. (2017) Down syndrome and fragile X syndrome in a Colombian woman: case report. J Appl Res Intellect Disabil, 30:970-974.

14.

Schaefer

, Mendelsohn

(2008) Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med, 10:4-12.

15.

Zhang

, Wang

, Li

, et al. (2018) Clinical feature of infertile men carrying balanced translocations involving chromosome 10: case series and a review of the literature. Medicine (Baltimore), 97:e0452.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.06 MB