Clinical Approach to a child with Poikiloderma: A case report

Rothmund-Thomson Syndrome is a rare autosomal recessive condition presenting usually in infancy that can be diagnosed based on time of onset, spreading and appearance of the poikiloderma.The purpose of reporting this case is to highlight the clinical approach to a child who presents with the features of poikiloderma.

Arterial Tortuosity Syndrome

A rare autosomal recessive condition, Arterial tortuosity syndrome (ATS) presents with ectactic blood vessels, cutaneous laxity, and bowel rupture. We report a case of an asymptomatic infant with arterial tortuosity syndrome who presented with left ventricular hypertrophy without any obvious obstruction to the outflow tract.

Prevalence and cardiometabolic correlates of ketohexokinase gene variants among UK Biobank participants

Essential fructosuria (EF) is a benign, asymptomatic, autosomal recessive condition caused by loss-of-function variants in the ketohexokinase gene and characterized by intermittent appearance of fructose in the urine. Despite a basic understanding of the genetic and molecular basis of EF, relatively little is known about the long-term clinical consequences of ketohexokinase gene variants. We examined the frequency of ketohexokinase variants in the UK Biobank sample and compared the cardiometabolic profiles of groups of individuals with and without these variants alone or in combination. Study cohorts consisted of groups of participants defined based on the presence of one or more of the five ketohexokinase gene variants tested for in the Affymetrix assays used by the UK Biobank. The rs2304681:G>A (p.Val49Ile) variant was present on more than one-third (36.8%) of chromosomes; other variant alleles were rare (<1%). No participants with the compound heterozygous genotype present in subjects exhibiting the EF phenotype in the literature (Gly40Arg/Ala43Thr) were identified. The rs2304681:G>A (p.Val49Ile), rs41288797 (p.Val188Met), and rs114353144 (p.Val264Ile) variants were more common in white versus non-white participants. Otherwise, few statistically or clinically significant differences were observed after adjustment for multiple comparisons. These findings reinforce the current understanding of EF as a rare, benign, autosomal recessive condition.

Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel’s aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.

Atypical presentation of cystic fibrosis at 70 years of age

Cystic fibrosis (CF) is an autosomal recessive condition, mostly diagnosed in infancy. It is uncommon for adults to be diagnosed with CF, especially after the age of 65. Individuals, who are diagnosed later in life, usually have milder disease and single organ involvement which can be challenging for clinicians to diagnose. Adult CF patients are more likely to be pancreatic sufficient. They have predominantly upper lobe bronchiectasis, lower incidence of Pseudomonas aeruginosa compared with Staphylococcus aureus and are more likely to have mutations other than ΔF508.

Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels

PurposePrenatal genetic carrier screening can identify parents at risk of having a child affected by a recessive condition. However, the conditions/genes most appropriate for screening remain a matter of debate. Estimates of carrier rates across genes are needed to guide construction of carrier screening panels.MethodsWe leveraged an exome sequencing database (n=123,136) to estimate carrier rates across 6 major ancestries for 416 genes associated with severe recessive conditions.Results36.5% (East Asian) to 65% (Ashkenazi Jewish) of individuals are variant carriers in at least one of the 416 genes. For couples, screening all 416 genes would identify 0.4-2.8% of couples as being at-risk for having a child affected by one of these conditions. Screening just the 47 genes with carrier rate > 1.0% would identify more than 85% of these at-risk couples. An ancestry-specific panel designed to capture genes with carrier rates > 1.0% would include 6 to 30 genes, while a comparable pan-ethnic panel would include 47 genes.ConclusionOur work guides the design of carrier screening panels and provides data to assist in counseling prospective parents. Our results highlight a high cumulative carrier rate across genes, underscoring the need for careful selection of genes for screening.