@article {101, title = {A novel missense variant in the PNPLA1 gene underlies congenital ichthyosis in three consanguineous families.}, journal = {J Eur Acad Dermatol Venereol}, volume = {30}, year = {2016}, month = {2016 Dec}, pages = {e210-e213}, keywords = {Amino Acid Sequence, Consanguinity, Female, Genes, Recessive, Humans, Ichthyosiform Erythroderma, Congenital, Lipase, Male, Mutation, Missense, Pakistan, Pedigree, Sequence Homology, Amino Acid}, issn = {1468-3083}, doi = {10.1111/jdv.13540}, author = {Ahmad, F and Ansar, M and Mehmood, S and Izoduwa, A and Lee, K and Nasir, A and Abrar, M and Mehmood, S and Ullah, A and Aziz, A and Smith, J D and Shendure, J and Bamshad, M J and Nicekrson, D A and Santos-Cortez, R L P and Leal, S M and Ahmad, W} } @article {111, title = {Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections.}, journal = {Clin Genet}, volume = {89}, year = {2016}, month = {2016 06}, pages = {719-23}, abstract = {

Marfan syndrome (MFS) due to mutations in FBN1 is a known cause of thoracic aortic aneurysms and acute aortic dissections (TAAD) associated with pleiotropic manifestations. Genetic predisposition to TAAD can also be inherited in families in the absence of syndromic features, termed familial TAAD (FTAAD), and several causative genes have been identified to date. FBN1 mutations can also be identified in FTAAD families, but the frequency of these mutations has not been established. We performed exome sequencing of 183 FTAAD families and identified pathogenic FBN1 variants in five (2.7\%) of these families. We also identified eight additional FBN1 rare variants that could not be unequivocally classified as disease-causing in six families. FBN1 sequencing should be considered in individuals with FTAAD even without significant systemic features of MFS.

}, keywords = {Adult, Aged, Aneurysm, Dissecting, Aortic Aneurysm, Thoracic, Exome, Family Health, Female, Fibrillin-1, Genetic Predisposition to Disease, Humans, Male, Marfan Syndrome, Middle Aged, Mutation, Pedigree, Sequence Analysis, DNA}, issn = {1399-0004}, doi = {10.1111/cge.12702}, author = {Regalado, E S and Guo, D C and Santos-Cortez, R L P and Hostetler, E and Bensend, T A and Pannu, H and Estrera, A and Safi, H and Mitchell, A L and Evans, J P and Leal, S M and Bamshad, M and Shendure, J and Nickerson, D A and Milewicz, D M} } @article {155, title = {Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Aug}, pages = {514-22}, abstract = {

BACKGROUND: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS.

METHODS: We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off.

RESULTS: We identified presumed causal variants in 62\% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34\% of individuals have a {\textquoteright}pure JS{\textquoteright} phenotype. Retinal disease is present in 30\% of individuals, renal disease in 25\%, coloboma in 17\%, polydactyly in 15\%, liver fibrosis in 14\% and encephalocele in 8\%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes.

CONCLUSIONS: This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.

}, keywords = {Abnormalities, Multiple, Cerebellum, Cohort Studies, DNA Mutational Analysis, Eye Abnormalities, Genetic Association Studies, Genetic Heterogeneity, Humans, Kidney Diseases, Cystic, Models, Theoretical, Pedigree, Retina, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103087}, author = {Bachmann-Gagescu, R and Dempsey, J C and Phelps, I G and O{\textquoteright}Roak, B J and Knutzen, D M and Rue, T C and Ishak, G E and Isabella, C R and Gorden, N and Adkins, J and Boyle, E A and de Lacy, N and O{\textquoteright}Day, D and Alswaid, A and Ramadevi A, Radha and Lingappa, L and Louren{\c c}o, C and Martorell, L and Garcia-Cazorla, {\`A} and Ozy{\"u}rek, H and Halilo{\u g}lu, G and Tuysuz, B and Top{\c c}u, M and Chance, P and Parisi, M A and Glass, I A and Shendure, J and Doherty, D} }