Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.

BACKGROUND: Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described. METHODS AND RESULTS: This study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1(bat/bat) mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome. CONCLUSIONS: The milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS-FREM complex diseases.

Trends in telehealth versus on-site clinical genetics appointments in Manitoba: a comparative study.

Telehealth involves the use of information and communications technology to deliver health services to patients over distance. Canada is well suited to benefit from telehealth since many individuals live in remote, rural and isolated locations. Manitoba is the easternmost prairie province and MBTelehealth is an active Canadian program that currently has 105 sites in 73 communities. Although studies of patient satisfaction comparing telehealth to on-site clinical visits have been conducted, a comparative study of the types of genetics patients seen via these two modalities has not been performed previously. In this study we: (1) examined the uptake of telehealth in Genetics in Manitoba; (2) contrasted telehealth usage in Genetics with other clinical programs; and (3) performed a comparative study of the types of Genetics referrals seen in 2008 on-site versus via telehealth. Results indicate the uptake of telehealth is increasing and has made genetics outreach clinics unnecessary. The Program of Genetics and Metabolism is consistently one of the top ten utilizers of telehealth within the province. With respect to discipline, chi square analysis revealed the trends were not significantly different for on-site and telehealth encounters, with prenatal referrals being the most common and Hereditary Breast and Ovarian Cancer referrals being the least common. Referrals within each discipline varied depending on the need for fetal assessment and physical examination. Telehealth was utilized regularly for test results sessions across all disciplines.

Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly.

Recessive mutations in FRAS1-related extracellular matrix 1 (FREM1) are associated with two rare genetic disorders, Manitoba-oculo-tricho-anal (MOTA) and bifid nose with or without anorectal and renal anomalies (BNAR). Fraser syndrome is a more severe disorder that shows phenotypic overlap with both MOTA and anorectal and renal anomalies and results from mutations in FRAS1, FREM2 and GRIP1. Heterozygous missense mutations in FREM1 were reported in association with isolated trigonocephaly with dominant inheritance and incomplete penetrance. Moreover, large deletions encompassing FREM1 have been reported in association with a syndromic form of trigonocephaly and were designated as trigonocephaly type 2. Trigonocephaly results from premature closure of the metopic suture and typically manifests as a form of nonsyndromic craniosynostosis. We report on 20 patients evaluated for developmental delay and without abnormal metopic suture. Chromosomal microarray analysis revealed heterozygous FREM1 deletions in 18 patients and in 4 phenotypically normal parents. Two patients were diagnosed with MOTA and had homozygous FREM1 deletions. Therefore, although our results are consistent with the previous reports of homozygous deletions causing MOTA, we report no association between heterozygous FREM1 deletions and trigonocephaly in this cohort.

Increased nuchal translucency thickness: a potential indicator for Ritscher-Schinzel syndrome.

OBJECTIVE: The Ritscher-Schinzel syndrome (RSS), also known as the 3C syndrome, is an autosomal recessive disorder classically comprising craniofacial, cerebellar and cardiac defects. The underlying molecular etiology remains unknown; therefore, prenatal diagnosis of recurrences depends on identification of the associated structural anomalies on second trimester ultrasound examination. Identification of recurrences using first-trimester ultrasound has not been reported previously. METHODS: Two women who presented at our center with fetal nuchal abnormalities on first trimester ultrasound went on to have children with RSS. One of the women had also undergone a previous pregnancy termination for fetal anomalies consistent with RSS. The ultrasound findings and details of these 3 cases were reviewed. RESULTS: Both cases of RSS and the third suspected case were found to have nuchal abnormalities on first-trimester scan. All went on to develop malformations consistent with RSS detectable on second-trimester ultrasound. The later 2 cases continued to term and the children had facial characteristics consistent with RSS. CONCLUSION: First-trimester ultrasound assessment of nuchal translucency could be considered as a method for identifying sib recurrences of RSS. In addition, RSS should be on the differential diagnosis when increased nuchal translucency is seen on first-trimester scan.

Parental Decision Making Regarding the Disclosure or Nondisclosure of a Mutation-Positive BRCA1/2 Test Result to Minors.

PURPOSE/OBJECTIVES: To gain insight into parental decision making regarding the disclosure or nondisclosure of a mutation-positive BRCA1/2 test result to minors.
. RESEARCH APPROACH: A qualitative study based on Heidegger hermeneutic phenomenology was undertaken to explore the lived experience of parental decision making regarding high-risk BRCA1/2 disclosure.
. SETTING: The study's recruitment site was a western Canadian hereditary breast and ovarian cancer clinic.
. PARTICIPANTS: Fifteen female mutation-positive BRCA1/2 carriers who had at least one child aged 6-18 years.
. METHODOLOGIC APPROACH: The use of a demographic questionnaire, semistructured interviews, and conversation summaries were employed to gain an understanding of participants' lived experience. van Manen's selective approach was used to conduct a thematic analysis.
. FINDINGS: Collectively, parents wanted clinicians to discuss implications of disclosing and not disclosing a mutation-positive BRCA1/2 test result to minors in greater detail. The findings were categorized under the following emergent themes. CONCLUSIONS: Participants' stories identified the need for auxiliary support pertaining to the decision-making process and suggested ways in which parental support may be coordinated.
. INTERPRETATION: Oncology nurses with advanced genetics training should assist mutation-positive BRCA1/2 carriers in meeting their genetic risk information needs; this requires nurses to stay informed about a multitude of issues that affect this population of patients.

Smith-Lemli-Opitz syndrome: new mutation with a mild phenotype.

Smith-Lemli-Opitz syndrome (SLOS) (Online Mendelian Inheritance in Man, OMIM, 2001, http://www.ncbi.nlm.nih.gov/omim/ for SLOS, MIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3beta-hydroxysterol Delta(7)-reductase gene, DHCR7. We report on a female infant with an exceptionally mild phenotype of SLOS, in whom molecular studies identified a new mutation in DHCR7. The proposita initially presented with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2-3 syndactyly of her toes in both feet. The plasma cholesterol was borderline low at 2.88 mmol/L (normal 2.97-4.40 mmol/L). Elevated plasma 7-dehydrocholesterol level of 200.0 micromol/L confirmed the clinical diagnosis of SLOS. Molecular analysis demonstrated compound heterozygosity for IVS8-1G -->C and Y280C, a new missense mutation in DHCR7. Since the other mutation in this patient is a known null mutation, this newly discovered mutation is presumably associated with significant residual enzyme activity and milder expression of clinical phenotype.

Understanding the impact of 1q21.1 copy number variant.

BACKGROUND: 1q21.1 Copy Number Variant (CNV) is associated with a highly variable phenotype ranging from congenital anomalies, learning deficits/intellectual disability (ID), to a normal phenotype. Hence, the clinical significance of this CNV can be difficult to evaluate. Here we described the consequences of the 1q21.1 CNV on genome-wide gene expression and function of selected candidate genes within 1q21.1 using cell lines from clinically well described subjects. METHODS AND RESULTS: Eight subjects from 3 families were included in the study: six with a 1q21.1 deletion and two with a 1q21.1 duplication. High resolution Affymetrix 2.7M array was used to refine the 1q21.1 CNV breakpoints and exclude the presence of secondary CNVs of pathogenic relevance. Whole genome expression profiling, studied in lymphoblast cell lines (LBCs) from 5 subjects, showed enrichment of genes from 1q21.1 in the top 100 genes ranked based on correlation of expression with 1q21.1 copy number. The function of two top genes from 1q21.1, CHD1L/ALC1 and PRKAB2, was studied in detail in LBCs from a deletion and a duplication carrier. CHD1L/ALC1 is an enzyme with a role in chromatin modification and DNA damage response while PRKAB2 is a member of the AMP kinase complex, which senses and maintains systemic and cellular energy balance. The protein levels for CHD1L/ALC1 and PRKAB2 were changed in concordance with their copy number in both LBCs. A defect in chromatin remodeling was documented based on impaired decatenation (chromatid untangling) checkpoint (DCC) in both LBCs. This defect, reproduced by CHD1L/ALC1 siRNA, identifies a new role of CHD1L/ALC1 in DCC. Both LBCs also showed elevated levels of micronuclei following treatment with a Topoisomerase II inhibitor suggesting increased DNA breaks. AMP kinase function, specifically in the deletion containing LBCs, was attenuated. CONCLUSION: Our studies are unique as they show for the first time that the 1q21.1 CNV not only causes changes in the expression of its key integral genes, associated with changes at the protein level, but also results in changes in their known function, in the case of AMPK, and newly identified function such as DCC activation in the case of CHD1L/ALC1. Our results support the use of patient lymphoblasts for dissecting the functional sequelae of genes integral to CNVs in carrier cell lines, ultimately enhancing understanding of biological processes which may contribute to the clinical phenotype.

Concordance of three methods for palpebral fissure length measurement in the assessment of fetal alcohol spectrum disorder.

BACKGROUND: The assessment of individuals at risk of fetal alcohol spectrum disorders (FASD) includes the assessment of the craniofacial features that can result from prenatal alcohol exposure. The characteristic facial features of fetal alcohol syndrome (FAS) consist of short palpebral fissures, smooth or flattened philtrum, and thin vermilion border of the upper lip. There are various methods for measuring palpebral fissure lengths (PFLs) and it can be challenging for clinicians to obtain reproducibly accurate measurements. The development of the FAS Facial Photographic Analysis Software by the University of Washington FAS Diagnostic and Prevention Network (DPN) is one such means of improving the accuracy and reproducibility in these measurements. OBJECTIVES: To assess concordance across three methods of PFL measurement: 1) a clear plastic handheld ruler, 2) blunt precision slide calipers, and 3) digital photometric photography (FAS Facial Photographic Analysis Software). METHODS: The PFLs of 50 children (referred to the Clinic for Alcohol and Drug Exposed Children, CADEC) at Children's Hospital in Winnipeg and 50 adults from the University of Manitoba Medical Class of 2008 were measured once by a single clinician, using each of the three methods. The frequency and magnitude of discordance was tabulated. No method served as a gold-standard. RESULTS: The PFLs ranged from 20 to 32 mm. The ruler and photometric measures were concordant in 42% of the subjects. When measures were discordant, half the ruler measures were larger and half were smaller. The caliper measure was concordant with the photometric and ruler measures on 18% and 24% of the subjects, respectively. When measures were discordant, the caliper measures were almost always larger than the photometric and ruler method (0.5 to 2.5 mm larger, 83% and 95% of the time, respectively). The presence of epicanthal folds did not appear to be a factor that contributed to discordance. CONCLUSION: This study demonstrates the challenge in measuring the PFL, even when a single trained clinician is involved. Factors that can contribute to error include the subject's willingness to cooperate, ability to tolerate placement of the tool close enough to the eye to obtain an accurate measure, and precision of the tool. When controlling for the clinician performing the measurements and the quality of the photographs, the ruler and photometric measures were most concordant. The caliper measures tended to measure larger than the ruler and photometric measures.

Early-onset neurodegenerative disease of the cerebellum and motor axons.

We describe a novel hereditary neurodegenerative disease of infancy affecting an Aboriginal family from northern Manitoba, Canada. The parents are nonconsanguineous, without a family history of neurodegenerative diseases. Four of 10 siblings (three males and one female) presented with neurologic abnormalities including arthrogryposis, seizures, and severe developmental delay shortly after birth. In two children, cerebellar atrophy and mild cerebral atrophy were documented on neuroimaging. Two children, a boy who died at age 40 months and a girl who died at age 22 months, underwent muscle biopsies at 3 weeks and 4 months of age, respectively. The biopsies revealed fiber-size variability in the boy, and grouped atrophy with fiber-type grouping in the girl. Two boys who died at ages 7.5 and 37 months underwent autopsies that indicated severe atrophy of the cerebellar hemispheres (especially the inferior lobules and vermis), hypomyelination of white-matter fascicles in the striatum, severe atrophy of corticospinal tracts in the brainstem and spinal cord, and atrophy of the anterior spinal roots. In the spinal cord, motor neuron cell bodies and the posterior columns were spared. This clinical entity likely represents a novel neurodegenerative disease of the cerebellum and long motor axons.

Manitoba Oculotrichoanal (MOTA) syndrome: report of eight new cases.

The Manitoba Oculotrichoanal (MOTA) syndrome was initially described by Marles et al. [1992; Am J Med Genet 42: 793-799] in Aboriginal patients of the Island Lake region of Northern Manitoba. Characteristic findings in affected patients included unilateral upper eyelid coloboma or cryptophthalmus with ipsilateral aberrant anterior hairline pattern and anal anomalies. We describe here seven new patients of the same extended kindred of Cree/Ojibway ethnicity of the Island Lake region and an eighth patient of Caucasian Dutch parents with clinical findings consistent with the diagnosis of MOTA syndrome. Two of the patients have bilateral, instead of unilateral, abnormal anterior hairline patterns. Omphalocele, a feature previously not identified, is present in three of them. The most consistent features appear to be hypertelorism and a broad or notched tip of the nose. Due to the obvious clinical overlap with Fraser syndrome, FRAS1 gene was screened in two of the affected and no mutation was found [Slavotinek et al., submitted].

Humeroradial synostosis, ulnar aplasia and oligodactyly, with contralateral amelia, in a child with prenatal cocaine exposure.

Humeral "bifurcation" due to humeroradial synostosis, and amelia are both very rare limb anomalies. We report on a Canadian. Aboriginal boy with both these limb deficiencies. The family history was unremarkable, but he was exposed prenatally to cocaine at the time of limb development. Humeroradial synostosis with ulnar aplasia has been reported by several authors. The majority of cases are unilateral. When both upper limbs arms are involved, cases with oligodactyly often have asymmetrical limb deficiencies and have all been sporadic to date. Some appear to represent cases of the femur-fibula-ulna or FFU complex. Affected individuals with normal hands usually have symmetrical defects and show an autosomal recessive pattern of inheritance. Limb deficiencies have been reported in several infants exposed prenatally to cocaine and have been inducible in animal models. Most are terminal transverse defects or deficiencies of middle digits. When more than one limb is involved, the defects are usually asymmetric. Our case appears to be one of the most severely affected children reported to date.