Familial Intracranial Aneurysm in Newfoundland: Clinical and Genetic Analysis.

OBJECTIVE: Intracranial aneurysm (IA) is an expansion of the weakened arterial wall that is often asymptomatic until rupture, resulting in subarachnoid hemorrhage. Here we describe the high prevalence of familial IA in a cohort of Newfoundland ancestry. We began to investigate the genetic etiology of IA in affected family members, as the inheritance of this disease is poorly understood. METHODS: Whole exome sequencing was completed for a cohort of 12 affected individuals from two multiplex families with a strong family history of IA. A filtering strategy was implemented to identify rare, shared variants. Filtered variants were prioritized based on validation by Sanger sequencing and segregation within the families. RESULTS: In family R1352, six variants passed filtering; while in family R1256, 68 variants remained, so further filtering was pursued. Following validation by Sanger sequencing, top candidates were investigated in a set of population controls, namely, C4orf6 c.A1G (p.M1V) and SPDYE4c.C103T (p.P35S). Neither was detected in 100 Newfoundland control samples. CONCLUSION: Rare and potentially deleterious variants were identified in both families, though incomplete segregation was identified for all filtered variants. Alternate methods of variant prioritization and broader considerations regarding the interplay of genetic and environmental factors are necessary in future studies of this disease.

Prévalence d'anévrismes intracrâniens au sein de familles terre-neuviennes : une analyse clinique et génétique. Objectif : Un anévrisme intracrânien (AI) consiste en une expansion, souvent asymptomatique, d'une paroi artérielle affaiblie. La rupture qui peut s'ensuivre résultera en une hémorragie sous-arachnoïdienne. Nous voulons décrire ici la forte prévalence d'AI au sein de familles terre-neuviennes ayant des ancêtres communs. Nous avons débuté cette étude en étudiant l'étiologie génétique de l'AI chez les membres de ces familles affectés par cette déformation car l'hérédité des AI demeure encore mal comprise. Méthodes : Nous avons tout d'abord procédé au séquençage entier de l'exome d'un groupe de 12 sujets appartenant à deux familles dites « multiplexes ¼ présentant des antécédents notables d'AI. À cet égard, une stratégie de filtrage a été mise de l'avant afin d'identifier des variantes génétiques à la fois peu fréquentes et partagées. Nous avons ensuite privilégié et validé ces variantes filtrées en nous fondant sur la méthode de séquençage et de ségrégation de Sanger. Résultats : Dans la famille R1352, 6 variantes ont été sélectionnées par filtrage alors que 68 variantes l'ont été dans le cas de la famille R1256, ce qui fait que des tâches additionnelles de filtrage ont été menées. Une fois complétée notre validation par la méthode de Sanger, les meilleurs sujets ont fait l'objet d'un travail d'analyse au sein d'un groupe de témoins de la population, à savoir C4orf6 c.A1G (p. M1V) et SPDYE4c.C103T (p. P35S). À cet égard, aucune variante génétique n'a été détectée parmi 100 échantillons de témoins de Terre-Neuve. Conclusion : Bien qu'une ségrégation incomplète ait été effectuée pour toutes les variantes filtrées, des variantes génétiques peu fréquentes et potentiellement délétères ont été détectées au sein de ces deux familles. D'autres méthodes de priorisation des variantes génétiques, de même que des considérations d'ordre plus général en ce qui a trait à l'interaction entre les facteurs génétiques et les facteurs environnementaux, sont nécessaires si l'on veut étudier les AI dans le futur.

A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an adult-onset Idiopathic Interstitial Pneumonia (IIP) usually diagnosed between age 50 to 70 years. Individuals with Familial Pulmonary Fibrosis (FPF) have at least one affected first or second-degree relative and account for 0.5-20% of cases. METHODS: We ascertained and collected DNA samples from a large population-based cohort of IPF patients from Newfoundland, Canada. For each proband, a family history was documented and medical records were reviewed. Each proband was classified as familial (28 patients) or sporadic (50 patients) and all 78 probands were screened for variants in four highly penetrant, adult-onset PF genes (SFTPC, SFTPA2, TERT,TERC). RESULTS: Seventy-eight IPF probands were enrolled of whom 28 (35.9%) had a positive family history. These 28 familial patients led to the recruitment of an additional 49 affected relatives (total of 77 FPF patients). By age 60 years, 42% of the familial cohort had been diagnosed with PF compared with only 16% of the sporadic patient collection (χ2 = 8.77, p = 0.003). Mean age of diagnosis in the familial group was significantly younger than the sporadic group (61.4 years vs. 66.6 yrs, p = 0.012) with a wider age range of diagnosis (19-92 years compared with 47-82 years). Thirty-three of 77 (42.8%) FPF patients had a tissue diagnosis and all but five had usual interstitial pneumonia histology. Compared with other published case series, the familial IIP histologies were more homogeneous. Three of 28 familial probands (10.7%) and none of the 50 sporadic probands had pathogenic variants in the four genes tested. All three familial probands had mutations in TERT. Other phenotypes associated with telomerase deficiency were present in these families including cirrhosis, bone marrow hypoplasia and premature graying. Telomere length assays were performed on mutation carriers from two families and confirmed telomere-related deficiency. CONCLUSION: The proportion of familial cases in our cohort is higher than any previously reported estimate and we suggest that this is due to the fact that Newfoundland cohort is ethnically homogeneous and drawn from a founder population. In our patient collection, diagnosis with IPF prior to age 45 years predicted familial disease. In two of the three TERT mutation families, the pedigree appearance is consistent with genetic anticipation. In the other 25 FPF families negative for mutations in known PF genes, we did not identify other telomerase associated medical problems (bone marrow dysfunction, cirrhosis) and we hypothesize that there are novel PF genes segregating in our population.

Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder.

BACKGROUND: Recurrent microdeletions and microduplications of approximately 555 kb at 16p11.2 confer susceptibility to autism spectrum disorder (ASD) in up to 1% of ASD patients. No physical or behavioural features have been identified that distinguish these individuals as having a distinct ASD subtype, but clinical data are limited. METHODS: We report five autistic probands identified by microarray analysis with copy number variation (CNV) of 16p11.2 (three deletions, two duplications). Each patient was assessed for ASD and dysmorphic features. We also describe a deletion positive 26-month-old female who has developmental delay (DD) and autistic features. RESULTS: Proband 1 (female with ASD, de novo deletion) is not dysmorphic. Proband 2 (male with autism, de novo deletion) and proband 3 and his brother (males with autism, inherited deletions) are dysmorphic, but the two probands do not resemble one another. The mother of proband 3 has mild mental retardation (MR), minor dysmorphism and meets the criteria for ASD. Proband 4 (dysmorphic autistic male, de novo duplication) had a congenital diaphragmatic hernia. Proband 5 (non-dysmorphic ASD female with a duplication) has two apparently healthy duplication positive relatives. Probands 1 and 2 have deletion negative siblings with ASD and Asperger syndrome, respectively. Proband 6 (a female with DD and an inherited duplication) is dysmorphic, but has oligohydramnios sequence. CONCLUSIONS: The phenotypic spectrum associated with CNV at 16p11.2 includes ASD, MR/DD and/or possibly other primary psychiatric disorders. Compared with the microduplications, the reciprocal microdeletions are more likely to be penetrant and to be associated with non-specific major or minor dysmorphism. There are deletion positive ASD probands with a less severe phenotype than deletion negative ASD siblings underscoring the significant phenotypic heterogeneity.