Tanya N. Eble

Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia

Focal dermal hypoplasia is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular and dental malformations. We used array comparative genomic hybridization to identify a 219-kb deletion in Xp11.23 in two affected females. We sequenced genes in this region and found heterozygous and mosaic mutations in PORCN in other affected females and males, respectively. PORCN encodes the human homolog of Drosophila melanogaster porcupine, an endoplasmic reticulum protein involved in secretion of Wnt proteins.

Facial and physical features of Aicardi syndrome: Infants to teenagers

Aicardi syndrome is a sporadic disorder that affects primarily females and is hypothesized to be caused by heterozygous mutations in an X‐linked gene. Its main features include of a triad of infantile spasms, agenesis of the corpus callosum, and distinctive chorioretinal lacunae. Additional common findings include moderate to profound mental retardation, gray matter heterotopia, gyral anomalies, and vertebral and rib defects. To date, no consistent facial dysmorphisms have been described. We examined 40 girls with Aicardi syndrome and determined that consistent facial features appeared in over half the study participants and included a prominent premaxilla, upturned nasal tip, decreased angle of the nasal bridge, and sparse lateral eyebrows. Externally apparent microphthalmia was seen in 10/40 (25%). Various skin lesions (including multiple nevi, skin tags, hemangiomas, one giant melanotic nevus, and a history of a previously removed angiosarcoma) were present in 8/40 (20%). Hand abnormalities were seen in 3/40 (7.5%) and included camptodactyly, proximal placement of the thumb and hypoplasia of the fifth finger. This study clearly delineates the existence of a distinctive facial phenotype of Aicardi syndrome not previously described. We recommend that features of a prominent premaxilla with upturned nasal tip and vascular malformations/vascular tumors be added to the modified diagnostic criteria in order to improve the ability of geneticists to diagnose Aicardi syndrome.

Phenotype and Management of Aicardi Syndrome: New Findings from a Survey of 69 Children

Aicardi syndrome is a rare neurodevelopmental disorder characterized by agenesis of the corpus callosum, other developmental brain abnormalities, chorioretinal lacunae, and severe seizures. Current clinical knowledge is derived from small series that focus on these major defects. The authors performed a health survey on a large number of affected children to expand this knowledge and to uncover previously unrecognized features of Aicardi syndrome. Responses received from caregivers of 69 children with Aicardi syndrome met inclusion criteria for data analysis. Ages ranged from 5 months to 32 years (mean, 88 months). All subjects were girls, except for 1 boy with a 47,XXY karyotype. The authors found that the growth rate in Aicardi syndrome slows at age 10 years to below the 5th percentile and that weight gain slows at age 7 years to below the 25th percentile. The median age of survival was estimated at 18.5 (±4) years, more favorable than previously reported. The most common complication aside from seizures was gastrointestinal dysfunction, present in >90%. The results from this survey contribute new information on Aicardi syndrome that will benefit clinical management, and collected data will benefit phenotype-driven research toward its underlying cause.

Ophthalmologic findings in Aicardi syndrome

BACKGROUND Aicardi syndrome is a rare X-linked disorder that has been characterized classically by agenesis of the corpus callosum, seizures, and the finding of chorioretinal lacunae. This triad has been augmented more recently by central nervous system and ocular findings. The goal of this study was to determine how frequently other ophthalmologic findings are associated with Aicardi syndrome. METHODS A single ophthalmologist recorded the ocular and adnexal findings of 40 girls with this disorder at the annual meeting of an Aicardi syndrome family support group. For each subject, the examiner performed facial anthropometrics, portable biomicroscopy, and, where feasible, indirect ophthalmoscopy. RESULTS The most common findings were chorioretinal lacunae in 66 (88%) of 75 eyes and optic nerve abnormalities in 61 (81%) of 75 eyes. Other less common findings included persistent pupillary membrane in 4 (5%) of 79 eyes and anterior synechiae in 1 of 79 eyes (1%). CONCLUSIONS Although the ophthalmic hallmark and defining feature of Aicardi syndrome is the cluster of distinctive chorioretinal lacunae surrounding the optic nerve(s), the spectrum of ocular, papillary, and retinal anomalies varies widely, from nearly normal to dysplasia of the optic nerve and to severe microphthalmos.

A Mosaic 2q24.2 Deletion Narrows the Critical Region to a 0.4 Mb Interval That Includes TBR1, TANK, and PSMD14

Interstitial deletions involving 2q24 have been associated with a wide range of phenotypes including intellectual disability and short stature. To date, the smallest common region among reported cases of deletions in this region is approximately 2.65 Mb and contains 15 genes. In the present case report, we describe an 18‐year‐old male with mild intellectual disability, short stature, and mosaicism for a 0.422 Mb deletion on 2q24.2 that was diagnosed by comparative genomic hybridization and confirmed with fluorescent in situ hybridization (FISH). This deletion, which is present in approximately 61% of cells, includes three genes: TBR1, TANK, and PSMD14. The findings suggest that the critical region for intellectual disability and short stature in 2q24.2 can be narrowed to a 0.422 Mb segment. TBR1, a transcription factor involved in early cortical development, is a strong candidate for the intellectual disability phenotype seen in our patient and in patients with larger deletions in this region of the genome.

POLG mutation in a patient with cataracts, early-onset distal muscle weakness and atrophy, ovarian dysgenesis and 3-methylglutaconic aciduria

Mutations in POLG account for one of the most frequent nuclear encoded causes of mitochondrial disorders to date. Individuals harboring POLG mutations exhibit fairly heterogeneous clinical presentations leading to increasing difficulties in classifying these patients into defined clinical phenotypes. This study aims to investigate the molecular basis of a mitochondrial cytopathy in a patient with 3-methylglutaconic aciduria and to expand the clinical phenotype associated with POLG mutations. Clinical, molecular and genetic analyses as well as neurophysiological examinations were carried out for a 23-year-old woman of mixed Caucasian and Latin American ancestry with a history of cataracts diagnosed at age 1 year, she had onset of distal muscle weakness at age 2 years progressing to atrophy and ovarian dysgenesis at puberty. The patient was found to have 3-methylglutaconic acid with normal 3 hydroxyisovaleric acid on urine organic acid analysis. POLG sequencing was done and a heterozygous variant, c.2851T>A (p.Y951N) was found which is predicted to be deleterious. There are limited reports of POLG mutations in individuals with 3-methylglutaconic aciduria. This case report of a young woman with a heterozygous mutation in POLG, presenting with muscle weakness and atrophy at a young age aims to aid clinicians in similar challenging diagnostic situations as well as enhances our understanding of POLG-related disease phenotypes.

A genome-wide screen for copy number alterations in Aicardi syndrome†

Aicardi syndrome is a severe neurodevelopmental disorder that affects females or rarely males with a 47,XXY karyotype. Therefore, it is thought to be caused by heterozygous defects in an essential X‐linked gene or by defects in an autosomal gene with sex‐limited expression. Because all reported cases are sporadic with one exception, traditional linkage analysis to identify the mutant gene is not possible, and the de novo mutation rate must be high. As an alternative approach to localize the mutant gene, we screened the DNA of 38 girls with Aicardi syndrome by high‐resolution, genome‐wide array comparative genomic hybridization for copy number gains and losses. We found 110 copy number variants (CNVs), 97 of which are known, presumably polymorphic, CNVs; 8 have been seen before in unrelated studies in unaffected individuals. Four previously unseen CNVs on autosomes were each inherited from a healthy parent. One subject with Aicardi syndrome had a de novo loss of X‐linked copy number in a region without known genes. Detailed analysis of this and flanking regions did not reveal CNVs or mutations in annotated genes in other affected subjects. We conclude that, in this study population of 38 subjects, Aicardi syndrome is not caused by CNVs detectable with the high‐resolution array platform that was used.

The practice of adult genetics: A 7-year experience from a single center†

The purpose of our study is to familiarize the reader with genetic disorders commonly seen in adults and identify challenges and barriers that limit provision of services. We conducted a retrospective chart analysis of patients seen in the adult Genetics clinics from January 2004 to December 2010 in a metropolitan medical center consisting of an academic private clinic and a county hospital clinic. During the study period, a total of 1,552 patients (n = 1,108 private clinic patients; n = 444 county clinic patients) were evaluated and managed. Of these, 790 and 280 were new patient visits at the private clinic and county clinic, respectively. Approximately 35% (374/1,070) of new patients were seen for cancer‐related indications, while neurological indications accounted for approximately 14% (153/1,070) in both clinics. Cardiology‐related indications accounted for approximately 13% (145/1,070) of patients, followed closely by chromosomal and syndromic indications for which almost 9% (96/1,070) of new patients were seen. Approximately 8% (90/1,070) of new patients were seen for musculoskeletal indications. We saw increased clinic growth during the study period and found that the most common indications for referral are: (1) Personal/family history of cancer (2) neurological (3) cardiovascular (CV) (4) chromosomal/syndromic and (5) musculoskeletal. A number of challenges were identified, including coordination of services, feasibility of testing, and an overall higher complexity of care with increased clinic scheduling time requirements. Through this review, we demonstrate the demand for adult genetics services and propose some guidelines to address the challenges of management in the adult genetics patient population.

Development and evaluation of a genomics training program for community health workers in Texas

PurposeGenomics services have the potential to reduce incidence and mortality of diseases by providing individualized, family health history (FHH)-based prevention strategies to clients. These services may benefit from the involvement of community health workers (CHWs) in the provision of FHH-based genomics education and services, as CHWs are frontline public health workers and lay health educators, who share similar ethnicities, languages, socioeconomic statuses, and life experiences with the communities they serve. We developed, implemented, and evaluated the FHH-based genomics training program for CHWs.MethodsThis theory- and evidence-based FHH-focused genomics curriculum was developed by an interdisciplinary team. Full-day workshops in English and Spanish were delivered to 145 Texas CHWs (91.6% were Hispanic/black). Preworkshop, postworkshop, and 3-month follow-up data were collected.ResultsCHWs significantly improved their attitudes, intention, self-efficacy, and knowledge regarding adopting FHH-based genomics into their practice after the workshops. At 3-month follow-up, these scores remained higher, and there was a significant increase in CHWs’ genomics practices.ConclusionThis FHH-based genomics training successfully educated Texas CHWs, and the outcomes were promising. Dissemination of training to CHWs in and outside of Texas is needed to promote better access to and delivery of personalized genomics services for the lay and underserved communities.

Adult Presentation of X-Linked Conradi-Hünermann-Happle Syndrome

Conradi‐Hünermann‐Happle syndrome, or X‐linked dominant chondrodysplasia punctata type 2 (CDPX2), is a genodermatosis caused by mutations in EBP. While typically lethal in males, females with CDPX2 generally manifest by infancy or childhood with variable features including congenital ichthyosiform erythroderma, chondrodysplasia punctata, asymmetric shortening of the long bones, and cataracts. We present a 36‐year‐old female with short stature, rhizomelic and asymmetric limb shortening, severe scoliosis, a sectorial cataract, and no family history of CDPX2. Whole exome sequencing (WES) revealed a p.Arg63del mutation in EBP, and biochemical studies confirmed a diagnosis of CDPX2. Short stature in combination with ichthyosis or alopecia, cataracts, and limb shortening in an adult should prompt consideration of a diagnosis of CDPX2. As in many genetic syndromes, the hallmark features of CDPX2 in pediatric patients are not readily identifiable in adults. This demonstrates the utility of WES as a diagnostic tool in the evaluation of adults with genetic disorders.