Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFß signaling in FTAAD.

BACKGROUND: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFß) signaling (TGFß receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK). METHODS AND RESULT: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFß signaling pathway. CONCLUSIONS: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFß signaling.

Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.

Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available. SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription. The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity. The identification of SMARCA2 mutations in humans provides insight into the function of the Snf2 helicase family.

Systematic search for neutropenia should be part of the first screening in patients with poikiloderma.

Poikiloderma occurs in a number of hereditary syndromes, the best known of which is Rothmund-Thomson syndrome (RTS). Differential diagnoses include Dyskeratosis Congenita (DC) with high genetic heterogeneity and Clericuzio-type Poikiloderma with Neutropenia (CPN) due to mutations in the C16orf57 gene. Mutations in the RECQL4 gene are only observed in two thirds of RTS patients. In this study, 10 patients referred for syndromic poikiloderma and negative for RECQL4 sequencing analysis were investigated for C16orf57 mutations. Two C16orf57 heterozygous nonsense mutations (p.W81X and p.Y89X) were identified in a 5-year-old female child presenting with generalized poikiloderma, dental dysplasia, gingivitis, nail dystrophy, palmoplantar keratoderma and pachyonychia of the great toenails. Previously undetected and silent neutropenia was evidenced after C16orf57 molecular analysis. Neutropenia was absent in the C16orf57-negative patients. This report confirms that neutrophil count should be performed in all patients with poikiloderma to target the C16orf57 gene sequencing analysis, prior to RECQL4 analysis.

Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia.

BACKGROUND: Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2). METHODS: Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19). RESULTS: The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features. CONCLUSIONS: It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

Nicolaides-Baraitser syndrome: Delineation of the phenotype.

Nicolaides-Baraitser syndrome (NBS) is an infrequently described condition, thus far reported in five cases. In order to delineate the phenotype and its natural history in more detail, we gathered data on 18 hitherto unreported patients through a multi-center collaborative study, and follow-up data of the earlier reported patients. A detailed comparison of the 23 patients is provided. NBS is a distinct and recognizable entity, and probably has been underdiagnosed until now. Main clinical features are severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time. The main differential diagnosis is Coffin-Siris syndrome. There is no important gender difference in occurrence and frequency of the syndrome, and all cases have been sporadic thus far. Microarray analysis performed in 14 of the patients gave normal results. Except for the progressive nature there are no clues to the cause.

Assessing the impact of FOXP1 mutations on developmental verbal dyspraxia.

Neurodevelopmental disorders that disturb speech and language are highly heritable. Isolation of the underlying genetic risk factors has been hampered by complexity of the phenotype and potentially large number of contributing genes. One exception is the identification of rare heterozygous mutations of the FOXP2 gene in a monogenic syndrome characterised by impaired sequencing of articulatory gestures, disrupting speech (developmental verbal dyspraxia, DVD), as well as multiple deficits in expressive and receptive language. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerisation. FOXP1, the most closely related member of this subgroup, can directly interact with FOXP2 and is co-expressed in neural structures relevant to speech and language disorders. Moreover, investigations of songbird orthologues indicate that combinatorial actions of the two proteins may play important roles in vocal learning, leading to the suggestion that human FOXP1 should be considered a strong candidate for involvement in DVD. Thus, in this study, we screened the entire coding region of FOXP1 (exons and flanking intronic sequence) for nucleotide changes in a panel of probands used earlier to detect novel mutations in FOXP2. A non-synonymous coding change was identified in a single proband, yielding a proline-to-alanine change (P215A). However, this was also found in a random control sample. Analyses of non-coding SNP changes did not find any correlation with affection status. We conclude that FOXP1 mutations are unlikely to represent a major cause of DVD.

Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits.

FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.

Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors.

The objective of this document is to provide health care professionals with recommendations for genetic counseling and testing of individuals with a suspected or confirmed diagnosis of Fabry disease, with a family history of Fabry disease, and those identified as female carriers of Fabry disease. These recommendations are the opinions of a multicenter working group of genetic counselors, medical geneticists, and other health professionals with expertise in Fabry disease counseling, as well as an individual with Fabry disease who is a founder of a Fabry disease patient advocacy group in the United States. The recommendations are U.S. Preventive Task Force Class III, and they are based on clinical experience, a review of pertinent English-language articles, and reports of expert committees. This document reviews the genetics of Fabry disease, the indications for genetic testing and interpretation of results, psychosocial considerations, and references for professional and patient resources. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a healthcare provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.