The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly

Varga, Elizabeth; Pastore, Matthew; Prior, Thomas W.; Herman, Gail E.; McBride, Kim L.

doi:10.1097/gim.0b013e31818fd762

Cited by 259 publications

(198 citation statements)

References 24 publications

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“…62 In addition to the previously mentioned studies, four other reported studies have looked at PTEN mutations in cohorts of persons with ASDs. 56,[63][64][65] The collective data from these studies identified 15 of 318 individuals (5%) with ASDs who had pathogenic PTEN mutations. Although most of these studies did not select for patients with ASDs with macrocephaly, retrospective analysis showed that macrocephaly was present in all positive cases.…”

Section: Single-gene Disordersmentioning

confidence: 99%

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

Schaefer

Mendelsohn

2013

Genetics in Medicine

453

393

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Autism spectrum disorders (ASDs), also known as pervasive developmental disorders, are a behaviorally defined group of neurodevelopmental disorders that are usually diagnosed in early childhood. They are characterized by varying degrees of limitations in communication and social interaction and by atypical, repetitive behaviors with an onset before 3 years of age. The phenotype of ASDs is extremely heterogeneous, with differences from person to person in a wide range of symptoms and severity as well as differences between the various subtypes of ASDs (e.g., autistic disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified).Multiple lines of epidemiologic evidence support the strong role of genetics in the etiology of ASDs. 1-3 Results of population studies of unselected cases of autism are most consistent with multifactorial inheritance. Until quite recently, the accepted recurrence risk for full siblings of a child with autism has been in the range of 3-10%. [4][5][6] Overall, only 2-3% of families have more than one affected child (possibly because of voluntary avoidance of pregnancy after a child is diagnosed). Most studies have reported a sex bias in the recurrence risk in keeping with the presumption of a "multifactorial" mode of inheritance (higher risk if the affected person is of the less commonly affected sex). As such, the reported risk is 7% of another affected child if the first affected child is female and 4% if the first affected child is male. 7 If multiple children (two or more) have autism, the recurrence risk is on the order of 33-50% for any future pregnancy. 7 Two recent studies 8,9 have reported even higher recurrence risks of 11 and 19% with single-sibling involvement. The first 8 was a retrospective self-enrolled/self-identified study using an interactive website. The diagnosis was confirmed, but the identification of second siblings may be a source of ascertainment bias. The second 9 was an international multisite prospective study in 664 families with a calculated 19% recurrence risk. Interestingly, the typically reported sex bias was not noted in one of these studies. 8 Both were single studies that bear replication.The autism spectrum disorders are a collective of conditions that have in common impaired socialization and communication in association with stereotypic behaviors. The reported incidence of autism spectrum disorders has increased dramatically over the past two decades. In addition, increased attention has been paid to these conditions by both lay and professional groups. These trends have resulted in an increase in the number of referrals to clinical geneticist for the evaluation of persons with autism spectrum disorders. The primary roles of the geneticist in this process are to define etiology when possible, to provide genetic counseling, and to contribute to case management. In deciding on the appropriate evaluation for a particular patient, the geneticist will consider a host of factors: (i) ensuring an accurate diagnosis of autism befor...

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Section: Single-gene Disordersmentioning

confidence: 99%

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

Schaefer

Mendelsohn

2013

Genetics in Medicine

453

393

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“…5,26,27 As the final exon in PTEN, missense mutations in this region would be predicted to only cause a slight alteration in protein structure and function. All three patients with exon 9 missense mutations and normal OFC had an invasive cancer that led their clinicians to consider a diagnosis of PHTS, but none had a family history that would have caused increased suspicion for PHTS before their cancers were diagnosed.…”

Section: Resultsmentioning

confidence: 99%

Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model

et al. 2011

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PTEN Hamartoma Tumour Syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and other conditions resulting from germline mutation of the PTEN tumour suppressor gene. Although macrocephaly, presumably due to megencephaly, is found in both CS and BRRS, the prevalence and degree have not been formally assessed in PHTS. We evaluated head size in a prospective nested series of 181 patients found to have pathogenic germline PTEN mutations. Clinical data including occipital-frontal circumference (OFC) measurement were requested for all participants. Macrocephaly was present in 94% of 161 evaluable PHTS individuals. In patients r18 years, mean OFC was +4.89 standard deviations (SD) above the population mean with no difference between genders (P¼0.7). Among patients 418 years, average OFC was 60.0 cm in females and 62.8 cm in males (Po0.0001). To systematically determine whether macrocephaly was due to megencephaly, we examined Pten M3M4 missense mutant mice generated and maintained on mixed backgrounds. Mice were killed at various ages, brains were dissected out and weighed. Average brain weight for Pten M3M4 homozygous mice (N¼15) was 1.02 g compared with 0.57 g for heterozygous mice (N¼29) and 0.49 g for wild-type littermates (N¼24) (Po0.0001). Macrocephaly, secondary to megencephaly, is an important component of PHTS and more prevalent than previously appreciated. Patients with PHTS have increased risks for breast and thyroid cancers, and early diagnosis is key to initiating timely screening to reduce patient morbidity and mortality. Clinicians should consider germline PTEN testing at an early point in the diagnostic work-up for patients with extreme macrocephaly.

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“…The mechanisms involved are not understood and may be cell-type or tissue specific. Importantly, PTEN is associated with a subset of individuals with autism spectrum disorders (Butler et al 2005;Varga et al 2009;McBride et al 2010). This may be related to the function of PTEN in neuronal stem cells (Amiri et al 2012).…”

Section: Genome Maintenance and Human Diseasementioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly

Cited by 259 publications

References 24 publications

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model

Regulation of Recombination and Genomic Maintenance

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