the AJMG SEQUENCE
In this issue
RECENTLY DISCOVERED SYNDROME IS BETTER DESCRIBED
Sensi et al [p. 1096] report on the first cases of FGF3 compound heterozygotes affected with labyrinthine aplasia, microtia, and microdontia (LAMM) syndrome.
The recently identified disorder has thus far been associated with homozygous mutations in the FGF3 gene. LAMM syndrome's phenotype includes external ear abnormalities, small widely spaced teeth and labyrinthine aplasia.
The patients include 2 siblings from Albania and 1 child from Italy, all with clinical and radiological diagnosis of LAMM syndrome. In these patients, the researchers identify novel FGF3 mutations, p.W153VfsX51, p.Y106C, and p.Y49C, as well as recurrence of the previously reported nonsense mutation p.R104X. Unlike previously described cases, the siblings show hypoplasia/dysplasia of middle ear anatomical structures.
Figure 4. Microtia with absence of the superi-I or crus of anthelix (lop ear) and hyperangulat-I ed ear. Small widely spaced teeth.
RESEARCHERS EXPLORE LINK BETWEEN AORTIC VALVE DISEASE AND BICUSPID AORTIC VALVE
The relationship between aortic valve disease (AVD) and bicuspid aortic valve (BAV) and its morphology isn't based on shared underlying genetic influences, say Calloway et al [p. 1015].
To identify risk factors for AVD in individuals with BAV, the researchers studied 281 subjects from 226 families with history of BAV. The researchers gave all subjects echocardiography and defined AVD as stenosis and/or insufficiency and BAV morphology as right-left (RL), right-non (RN), or indeterminate. The researchers used variance components analysis to estimate heritability of AVD and BAV morphology and assessed AVD risk over time.
The researchers found BAV in 281 individuals, or 25%. Of those, 59% had AVD. The researchers also found absent to low heritability, indicating little evidence of underlying genetic effects, but a previous study by the researchers identified a I high heritability for BAV, they note. AVD was significantly associated with BAV morphology.
People with RN BAV are more likely to develop AVD as children, while people with RL BAV are more likely to develop AVD as adults, the researchers note.These results suggest BAV morphology may have predictive value for the time course of AVD, say researchers.
Figure 1. Diagram of j individuals included in j each study group. The I original study group of j 1,128 individuals was ultimately broken into 2 groups for analysis. Individuals were analyzed for AVD risk I analysis (n = 165) and I genetic concordance of BAV morphology (n = 29).
They recommend surveillance in pediatric patients with RN morphology every 2 years, and less aggressive monitoring for young children with RL BAV.
NEW DISORDER OF BRANCHIAL CLEFT DESCRIBED
Figure 1. The propositus and affected father showing major I findings.
Sampath et al [p. 976] report on what they believe is a new syndrome of the branchial cleft. The researchers describe the autosomal dominant disorder, named hypertelorism, preauricular sinus, punctal pits, and deafness (HPDD), in a three-generation family. Members are affected by a constellation of abnormalities, including preauricular sinus, punctal pits, hearing loss, hypertelorism, and abnormal palmar flexion creases. According to the researchers, none of the known syndromes involving the first branchial arch are a fit with these features.
HPDD is likely a new syndrome because its disease locus is linked to a region of the genome as yet unimplicated in syndromes with phenotypic similarities, although a causative mutation in this region could not be identified.
Through direct sequencing of their exons and by SNP-based linkage analysis, the researchers eliminated links between HPDD and 3 known candidate genes, EYA1, SIX1, and SIX5.They also,mapped the disorder to a novel locus at chromosome 14q31.1-31.3. Direct sequencing of the gene exons within the interval and a custom aCGH experiment did not show any pathogenic mutation or copy-number changes.
Further sequencing of 24 kb of promoter regions showed a novel polymorphism 1,249 bp upstream from the SELIL start codon that segregated with the disease haplotype. Cloning the novel polymorphism into luciferase reporter constructs resulted in a 20% reduction in the expression levels.
Further sequencing 24 kb of promoter regions within this defined interval identified a novel polymorphism upstream of SEL1L that showed modest effect in luciferase reporter constructs.
Because its effect on expression was small and this promoter variant was found in control populations, the researchers don't believe the SEL1L promoter variant causes the syndrome. The team says it hopes other clinicians will report similar patients and enable confirmation of the new syndrome.