Joan F. Atkin

Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly.

There is a strong genetic component to autism spectrum disorders (ASD), but due to significant genetic heterogeneity, individual genetic abnormalities contribute a small percentage to the overall total. Previous studies have demonstrated PTEN mutations in a sizable proportion of individuals with ASD or mental retardation/developmental delays (MR/DD) and macrocephaly that do not have features of Cowden or Bannayan–Riley–Ruvalcaba syndrome. This study was performed to confirm our previous results. We reviewed the charts of individuals who had PTEN clinical sequencing performed at our institution from January 2008 to July 2009. There were 93 subjects tested from our institution during that period. PTEN mutations were found in 2/39 (5.1%) ASD patients and 2/51 (3.9%) MR/DD patients. Three additional patients without mutations had no diagnostic information. Multiple relatives of individuals with a PTEN mutation had macrocephaly, MR, or early onset cancer (breast, renal, and prostate). Of those relatives tested, all had the familial PTEN mutation. None of the affected relatives had previously been diagnosed with Cowden or Bannayan–Riley–Ruvalcaba syndrome. We noted in our previous study several adult relatives without any findings who carried a mutation. Combined with data from our previous cohort, we have found PTEN mutations in 7/99 (7.1%) of individuals with ASD and 8/100 (8.0%) of individuals with MR/DD, all of whom had macrocephaly. We recommend testing for mutations in PTEN for individuals with ASD or MR/DD and macrocephaly. If mutations are found, other family members should be offered testing and the adults offered cancer screening if they have a PTEN mutation.

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect. Using whole-exome sequencing of three proband-parent trios, we identified de novo missense changes in the cytoplasmic actin–encoding genes ACTB and ACTG1 in one and two probands, respectively. Sequencing of both genes in 15 additional affected individuals identified disease-causing mutations in all probands, including two recurrent de novo alterations (ACTB, encoding p.Arg196His, and ACTG1, encoding p.Ser155Phe). Our results confirm that trio-based exome sequencing is a powerful approach to discover genes causing sporadic developmental disorders, emphasize the overlapping roles of cytoplasmic actin proteins in development and suggest that Baraitser-Winter syndrome is the predominant phenotype associated with mutation of these two genes.

Leigh Disease With Mitochondrial DNA A8344G Mutation: Case Report and Brief Review

Leigh disease, subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder often seen in infancy or childhood but rarely reported in adults. Genetic heterogeneity is well recognized, and the associated etiologies include both mitochondrial and nuclear DNA defects. We describe an infant presenting with developmental delay and then progressive multisystem disorder and neuroradiologic features of Leigh disease. He and his maternal relatives all have the A8344G mitochondrial DNA mutation. However, only minor clinical features are seen in his maternal relatives, with migraine being the most common problem. Additionally, the A8344G mitochondrial DNA mutation is associated with spinocerebellar degeneration, other nonspecific mitochondrial encephalomyopathies, atypical Charcot-Marie-Tooth disease, and progressive external ophthalmoplegia. The A8344G mitochondrial DNA mutation may present with Leigh disease or other different atypical clinical features without myoclonic epilepsy and ragged red fibers. (J Child Neurol 2003; 18: 62—64).

X-linked infantile periodic alternating nystagmus.

Objective: To describe the clinical and electrophysiological characterization of four family members from three generations who have X-linked infantile periodic alternating nystagmus (XIPAN). Methods: Complete clinical ophthalmological evaluation, pedigree analysis, electroretinograms (ERG), eye movement recordings (EMR), color vision, and fundus photography were performed on all subjects. Results: Three males in two generations and one female were examined. Clinical examinations showed a jerk/pendular nystagmus with a latent component, strabismus, and a significant refractive error in the three affected males, while the female had only myopic astigmatism. ERG, color contrast, and fundus examinations were normal in all four family members. All four family members showed EMR abnormalities with infantile jerk/dual jerk and pendular nystagmus waveforms. The female had nystagmus present on EMR only and all patients showed (a)periodicity to their nystagmus. Conclusions: In this family with no other congenital visual sensory system disease, affected males had obvious periodic alternating nystagmus, strabismus, and refractive errors, while the female had clinically ‘silent’ periodic nystagmus that is probably a marker for the carrier state.

Unexpected detection of dystrophin gene deletions by array comparative genomic hybridization

Array comparative genomic hybridization has increasingly become the standard of care to evaluate patients for genomic imbalance. As the patient population evaluated by microarray expands, there is certain to be an increase in the detection of unexpected, yet common diseases. When array results predict a late‐onset disorder or cancer predisposition, it becomes a challenge for physicians and counselors to adequately address with patients. Included in this study were three patients described with nonspecific phenotypic findings who underwent microarray testing to better define their disease etiology. An unexpected deletion within the dystrophin gene was observed in each case, despite that no patient was suspected of a dystrophinopathy at the time of testing. The patients included an 8‐day‐old male with a dystrophin deletion predictive of Becker muscular dystrophy, an 18‐month old female found to be the carrier of deletion, and a 4‐year‐8‐month‐old male with a deletion predictive of Duchenne muscular dystrophy. In this circumstance it becomes difficult to counsel the family, as well as to predict disease course when underlying medical conditions may exist. However, early detection may enable the patient to receive proactive treatment, and allows for screening of at‐risk family members. Ultimately, it is up to the clinician to promote informed decision‐making within the family prior to testing, and ensure that adequate counseling is provided during follow‐up.

Actin capping protein CAPZB regulates cell morphology, differentiation, and neural crest migration in craniofacial morphogenesis

CAPZB is an actin-capping protein that caps the growing end of F-actin and modulates the cytoskeleton and tethers actin filaments to the Z-line of the sarcomere in muscles. Whole-genome sequencing was performed on a subject with micrognathia, cleft palate and hypotonia that harbored a de novo, balanced chromosomal translocation that disrupts the CAPZB gene. The function of capzb was analyzed in the zebrafish model. capzb(-/-) mutants exhibit both craniofacial and muscle defects that recapitulate the phenotypes observed in the human subject. Loss of capzb affects cell morphology, differentiation and neural crest migration. Differentiation of both myogenic stem cells and neural crest cells requires capzb. During palate morphogenesis, defective cranial neural crest cell migration in capzb(-/-) mutants results in loss of the median cell population, creating a cleft phenotype. capzb is also required for trunk neural crest migration, as evident from melanophores disorganization in capzb(-/-) mutants. In addition, capzb over-expression results in embryonic lethality. Therefore, proper capzb dosage is important during embryogenesis, and regulates both cell behavior and tissue morphogenesis.

Microarray comparative genomic hybridization and cytogenetic characterization of tissue-specific mosaicism in three patients.

The presence of more than one cell line in an individual may often be missed by classical cytogenetic analysis due to a low percentage of affected cells or analysis of cells from an unaffected or less affected germ layer. Array comparative genomic hybridization (aCGH) from whole blood or tissue is an important adjunct to standard karyotyping due to its ability to detect genomic imbalances that are below the resolution of karyotype analysis. We report results from three unrelated patients in whom aCGH revealed mosaicism not identified by peripheral blood chromosome analysis. This study further illustrates the important application of aCGH in detecting tissue‐specific mosaicism, thereby leading to an improvement in the ability to provide a diagnosis for patients with normal chromosome analysis and dysmorphic features, congenital anomalies, and/or developmental delay.

A case of an atypically large proximal 15q deletion as cause for Prader-Willi syndrome arising from a de novo unbalanced translocation.

We describe an 11 month old female with Prader-Willi syndrome (PWS) resulting from an atypically large deletion of proximal 15q due to a de novo 3;15 unbalanced translocation. The 10.6 Mb deletion extends from the chromosome 15 short arm and is not situated in a region previously reported as a common distal breakpoint for unbalanced translocations. There was no deletion of the reciprocal chromosome 3q subtelomeric region detected by either chromosomal microarray or FISH. The patient has hypotonia, failure to thrive, and typical dysmorphic facial features for PWS. The patient also has profound global developmental delay consistent with an expanded, more severe, phenotype.

Multigeneration family with short stature, developmental delay, and dysmorphic features due to 4q27-q28.1 microdeletion.

Deletions of the long arm of chromosome 4 are rare but have been previously reported to be associated with craniofacial anomalies, digital anomalies, developmental delay, growth failure, and cardiovascular anomalies. Strehle et al. previously presented 20 patients with 4q deletions and began to construct a phenotype-genotype map for chromosome 4q. This report follows up on that work by providing clinical and molecular cytogenetic data on a three generation pedigree including seven patients with short stature, dysmorphic features, and developmental delay identified to have a 4q27-q28.1 microdeletion of approximately 5.68 Mb by oligonucleotide chromosomal microarray. This family represents a rare report of an inherited interstitial deletion of the long arm of chromosome 4. To our knowledge, only two cases have been previously reported. The contribution of candidate genes in the region is discussed.