Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val

Abstract

De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition. © 2012 Wiley Periodicals, Inc.

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

“…2D). Comparing the sperm data with observed births of CS, it is apparent that p.G12S is unexpectedly prevalent in CS compared with other p.G12 substitutions, which suggests that these other (more activating) mutations may be associated with a higher risk of demise during the pregnancy (33). In agreement with our finding that TBS are not uncommon in sperm, a total of six CS patients carrying similar mutations have been reported (Table S1).…”

“…In agreement with our finding that TBS are not uncommon in sperm, a total of six CS patients carrying similar mutations have been reported (Table S1). Strikingly, among patients diagnosed with HRAS mutations encoding p.G12V, five cases have been associated with TBS (four with c.35_36GC>TT and one with c.35_36GC>TA), whereas only a single patient carried the c.35G>T substitution (31)(32)(33). The predominance of the c.35_36GC>TT TBS among observed CS alleles supports the relevance of our sperm data, as this was the majority (21/30) of the TBS observed.…”

“…Other p.G12 mutations have also been described, including p.G12A, p.G12C, p.G12D, p.G12V, and p.G12E. These rarer alleles tend to be associated with more severe manifestations, often involving hypertrophic cardiomyopathy and resulting in neonatal mortality (31)(32)(33)(34), consistent with biochemical evidence that p.G12S is less activating than any other mutation at this codon (23,24).…”

Early-Lethal Costello Syndrome Due to Rare HRAS Tandem Base Substitution (c.35_36GC>AA; p.G12E)–Associated Pulmonary Vascular Disease

“…Moreover, the mutation G12V has been established as a consistent cause of early lethal Costello syndrome with cardiomyopathy [12]. Our patient is unique in that severe cardiomyopathy was not detected by echocardiogram.…”

Expanding the spectrum of IDH1 mutations in gliomas

“…Dinucleotide deletion/insertion mutations, or tandem base pair mutations, are uncommon genetic lesions in both human somatic and germline disease. 25 Only one dinucleotide deletion/insertion mutation of IDH1 has been reported previously in gliomas, in that case a (c.394_395CGdelinsGT, p.R132V) was identified in a study of 685 brain tumors, 8 the only reported example of the p.R132V mutation. These unusual dinucleotide mutations have also been seen as rare events in AML patients, and four instances of heterozygous dinucleotide deletion/ insertion mutation of IDH1 (c.395_396GTdelinsAC) as an alternate path to the IDH1 p.R132H mutant protein have been reported in a study of 416 Chinese AML patients.…”