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Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

Grillo E, Lo Rizzo C, Bianciardi L, Bizzarri V, Baldassarri M, Spiga O, Furini S, De Felice C, Signorini C, Leoncini S, Pecorelli A, Ciccoli L, Mencarelli MA, Hayek J, Meloni I, Ariani F, Mari F, Renieri A - PLoS ONE (2013)

Bottom Line: On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype.Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches.Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics, University of Siena, Siena, Italy.

ABSTRACT
Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

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Related in: MedlinePlus

Patient photographs and pedigree.In the pedigrees the two sisters couples are represented by grey circles (milder variant = Zappella Rett variant (Z-RTT)) and black circles (more severe phenotype = classical Rett (RTT)). Panel a) Sisters #139 and #138 at the age of 28 and 19, respectively, and pedigree. Presently, patient #139 is 40 years old and is still able to speak in short phrases. Although late stage RTT-associated motor deterioration began 10 years ago, she is still ambulatory. Her phenotype was previously described. [3], [35] Her sister, patient #138, is 29 years old and has never been able to walk unassisted. Ten years ago she developed spastic tetraplegia with contractures that are still present and are further deteriorating. Panel b) Sisters #896 and #897 at the age of 32 and 26, respectively, and pedigree. Presently, patient #896 is 39 year-old and is still able to walk and to speak in short phrases. She has a friendly behavior and was extremely cooperative during examinations. Her somatic parameters is in the mean range (Occipital-Frontal Circumference (OFC): 54.5 cm, 50–75th percentile; height 162 cm, 25–50th percentile; weight 63 Kg, Body Mass Index (BMI) = 24), she has a severe kyphosis and mild pes planus. She has no hand stereotypes and possesses good manual abilities, being able to make simple drawings, eat independently, dress and wash herself. She has never had epilepsy, gastroesophageal reflux, breathing disorders and cold extremities. She has bruxism and a high pain threshold. Her 34 year-old sister (patient #897) shows spastic tetraplegia with severe contractures and hyperventilation. She shows somatic hypoevolutism (OFC 51,5 cm, <3rd percentile; height 150 cm, <3rd percentile; weight 29 Kg, BMI = 13), lordosis, and mild pes planus. She has constant hand stereotypes (pill counting and hand-mouthing), sialorrhea, bruxism, epilepsy that was not controlled by therapy, and cold extremities. She has never been able to speak.
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pone-0056599-g001: Patient photographs and pedigree.In the pedigrees the two sisters couples are represented by grey circles (milder variant = Zappella Rett variant (Z-RTT)) and black circles (more severe phenotype = classical Rett (RTT)). Panel a) Sisters #139 and #138 at the age of 28 and 19, respectively, and pedigree. Presently, patient #139 is 40 years old and is still able to speak in short phrases. Although late stage RTT-associated motor deterioration began 10 years ago, she is still ambulatory. Her phenotype was previously described. [3], [35] Her sister, patient #138, is 29 years old and has never been able to walk unassisted. Ten years ago she developed spastic tetraplegia with contractures that are still present and are further deteriorating. Panel b) Sisters #896 and #897 at the age of 32 and 26, respectively, and pedigree. Presently, patient #896 is 39 year-old and is still able to walk and to speak in short phrases. She has a friendly behavior and was extremely cooperative during examinations. Her somatic parameters is in the mean range (Occipital-Frontal Circumference (OFC): 54.5 cm, 50–75th percentile; height 162 cm, 25–50th percentile; weight 63 Kg, Body Mass Index (BMI) = 24), she has a severe kyphosis and mild pes planus. She has no hand stereotypes and possesses good manual abilities, being able to make simple drawings, eat independently, dress and wash herself. She has never had epilepsy, gastroesophageal reflux, breathing disorders and cold extremities. She has bruxism and a high pain threshold. Her 34 year-old sister (patient #897) shows spastic tetraplegia with severe contractures and hyperventilation. She shows somatic hypoevolutism (OFC 51,5 cm, <3rd percentile; height 150 cm, <3rd percentile; weight 29 Kg, BMI = 13), lordosis, and mild pes planus. She has constant hand stereotypes (pill counting and hand-mouthing), sialorrhea, bruxism, epilepsy that was not controlled by therapy, and cold extremities. She has never been able to speak.

Mentions: Two pairs of sisters with discordant phenotype were enrolled in the study (Fig. 1a and 1b). Siblings #138 (classical RTT) and #139 (Z-RTT) possessed the same mutation in MECP2, c.1157del32, and showed a balanced XCI. The mutation was inherited from their unaffected mother, who had a completely skewed XCI. [3] Siblings #897 (classical RTT) and #896 (Z-RTT) had an apparently de novo MECP2 deletion including exon 3 and part of exon 4. [6] XCI status analysis in this couple of sister revealed balanced XCI in both. [6] The unrelated classical RTT individuals #138 and #897 could not speak and walk and had a profound intellectual deficit, while the Z-RTT individuals #139 and #896 could speak and walk and had a moderate intellectual disability (Z-RTT). We quantified the striking differences in somatic, neurodevelopmental, and neurovegetative features between the sisters using a previously described scoring system (score from 0- mildest end to 40- most severe end; mean classical RTT score of 27.5±5.3 and mean Z-RTT score of 13.8±5.9; a threshold of 20 divided classical RTT from Z-RTT). [7] According to this scoring system the classical RTT girls had a clinical score of 30 (#138) and 33 (#897), which lies within the range of scores for the most severe RTT outcomes. Conversely, the Z-RTT girls had a score of 10 (#139) and 7 (#896) indicating a milder, high functioning form of RTT (Table 1). [7] This study was approved by the institutional review board of the University of Siena (Siena, Italy). The parents of the patients have given written informed consent, as outlined in the PLOS consent form, to publication of their photograph. Participation in the study did not alter the standard of care.


Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

Grillo E, Lo Rizzo C, Bianciardi L, Bizzarri V, Baldassarri M, Spiga O, Furini S, De Felice C, Signorini C, Leoncini S, Pecorelli A, Ciccoli L, Mencarelli MA, Hayek J, Meloni I, Ariani F, Mari F, Renieri A - PLoS ONE (2013)

Patient photographs and pedigree.In the pedigrees the two sisters couples are represented by grey circles (milder variant = Zappella Rett variant (Z-RTT)) and black circles (more severe phenotype = classical Rett (RTT)). Panel a) Sisters #139 and #138 at the age of 28 and 19, respectively, and pedigree. Presently, patient #139 is 40 years old and is still able to speak in short phrases. Although late stage RTT-associated motor deterioration began 10 years ago, she is still ambulatory. Her phenotype was previously described. [3], [35] Her sister, patient #138, is 29 years old and has never been able to walk unassisted. Ten years ago she developed spastic tetraplegia with contractures that are still present and are further deteriorating. Panel b) Sisters #896 and #897 at the age of 32 and 26, respectively, and pedigree. Presently, patient #896 is 39 year-old and is still able to walk and to speak in short phrases. She has a friendly behavior and was extremely cooperative during examinations. Her somatic parameters is in the mean range (Occipital-Frontal Circumference (OFC): 54.5 cm, 50–75th percentile; height 162 cm, 25–50th percentile; weight 63 Kg, Body Mass Index (BMI) = 24), she has a severe kyphosis and mild pes planus. She has no hand stereotypes and possesses good manual abilities, being able to make simple drawings, eat independently, dress and wash herself. She has never had epilepsy, gastroesophageal reflux, breathing disorders and cold extremities. She has bruxism and a high pain threshold. Her 34 year-old sister (patient #897) shows spastic tetraplegia with severe contractures and hyperventilation. She shows somatic hypoevolutism (OFC 51,5 cm, <3rd percentile; height 150 cm, <3rd percentile; weight 29 Kg, BMI = 13), lordosis, and mild pes planus. She has constant hand stereotypes (pill counting and hand-mouthing), sialorrhea, bruxism, epilepsy that was not controlled by therapy, and cold extremities. She has never been able to speak.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585308&req=5

pone-0056599-g001: Patient photographs and pedigree.In the pedigrees the two sisters couples are represented by grey circles (milder variant = Zappella Rett variant (Z-RTT)) and black circles (more severe phenotype = classical Rett (RTT)). Panel a) Sisters #139 and #138 at the age of 28 and 19, respectively, and pedigree. Presently, patient #139 is 40 years old and is still able to speak in short phrases. Although late stage RTT-associated motor deterioration began 10 years ago, she is still ambulatory. Her phenotype was previously described. [3], [35] Her sister, patient #138, is 29 years old and has never been able to walk unassisted. Ten years ago she developed spastic tetraplegia with contractures that are still present and are further deteriorating. Panel b) Sisters #896 and #897 at the age of 32 and 26, respectively, and pedigree. Presently, patient #896 is 39 year-old and is still able to walk and to speak in short phrases. She has a friendly behavior and was extremely cooperative during examinations. Her somatic parameters is in the mean range (Occipital-Frontal Circumference (OFC): 54.5 cm, 50–75th percentile; height 162 cm, 25–50th percentile; weight 63 Kg, Body Mass Index (BMI) = 24), she has a severe kyphosis and mild pes planus. She has no hand stereotypes and possesses good manual abilities, being able to make simple drawings, eat independently, dress and wash herself. She has never had epilepsy, gastroesophageal reflux, breathing disorders and cold extremities. She has bruxism and a high pain threshold. Her 34 year-old sister (patient #897) shows spastic tetraplegia with severe contractures and hyperventilation. She shows somatic hypoevolutism (OFC 51,5 cm, <3rd percentile; height 150 cm, <3rd percentile; weight 29 Kg, BMI = 13), lordosis, and mild pes planus. She has constant hand stereotypes (pill counting and hand-mouthing), sialorrhea, bruxism, epilepsy that was not controlled by therapy, and cold extremities. She has never been able to speak.
Mentions: Two pairs of sisters with discordant phenotype were enrolled in the study (Fig. 1a and 1b). Siblings #138 (classical RTT) and #139 (Z-RTT) possessed the same mutation in MECP2, c.1157del32, and showed a balanced XCI. The mutation was inherited from their unaffected mother, who had a completely skewed XCI. [3] Siblings #897 (classical RTT) and #896 (Z-RTT) had an apparently de novo MECP2 deletion including exon 3 and part of exon 4. [6] XCI status analysis in this couple of sister revealed balanced XCI in both. [6] The unrelated classical RTT individuals #138 and #897 could not speak and walk and had a profound intellectual deficit, while the Z-RTT individuals #139 and #896 could speak and walk and had a moderate intellectual disability (Z-RTT). We quantified the striking differences in somatic, neurodevelopmental, and neurovegetative features between the sisters using a previously described scoring system (score from 0- mildest end to 40- most severe end; mean classical RTT score of 27.5±5.3 and mean Z-RTT score of 13.8±5.9; a threshold of 20 divided classical RTT from Z-RTT). [7] According to this scoring system the classical RTT girls had a clinical score of 30 (#138) and 33 (#897), which lies within the range of scores for the most severe RTT outcomes. Conversely, the Z-RTT girls had a score of 10 (#139) and 7 (#896) indicating a milder, high functioning form of RTT (Table 1). [7] This study was approved by the institutional review board of the University of Siena (Siena, Italy). The parents of the patients have given written informed consent, as outlined in the PLOS consent form, to publication of their photograph. Participation in the study did not alter the standard of care.

Bottom Line: On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype.Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches.Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics, University of Siena, Siena, Italy.

ABSTRACT
Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

Show MeSH
Related in: MedlinePlus