Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.

New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.

Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23.

Germline mutations in the gene CBL (Casitas B-lineage lymphoma), involved in the RAS-MAPK signaling pathway, have been found as a rare cause of the neuro-cardio-facial-cutaneous syndromes. Somatically acquired homozygous CBL mutations were initially identified in association with myeloproliferative disorders, particularly juvenile myelomonocytic leukemia (JMML). We describe a girl with a Noonan-like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL. She developed an ovarian mixed germ cell/teratoma with later occurrence of mature liver, omental, and ovarian teratomas. Copy neutral loss of heterozygosity for the CBL mutation due to acquired segmental uniparental disomy of 11q23 was observed in three teratomas, suggesting a specific association of CBL mutations in germ cell tumor predisposition.

15q overgrowth syndrome: a newly recognized phenotype associated with overgrowth, learning difficulties, characteristic facial appearance, renal anomalies and increased dosage of distal chromosome 15q.

Trisomy and tetrasomy of distal chromosome 15q have rarely been reported. Although most of the described patients have some learning difficulties and are overgrown, the phenotype associated with distal trisomy/tetrasomy 15q is uncertain due to the small numbers of reported cases and the common co-occurrence of additional chromosome deletions in many patients with trisomy 15q. We present five individuals with overgrowth, learning difficulties and increased dosage of distal 15q. Partial trisomy 15q was identified in four of these cases. Two were generated through recombination of a parental pericentric inversion and two were generated through malsegregation of a maternal balanced 14;15 reciprocal translocation. In all four cases the trisomy can be considered "pure" as the 14p and 15p monosomies will exert no phenotypic effect. Partial tetrasomy 15q, as the result of an analphoid supernumerary chromosome derived from an inverted duplication of distal 15q, was identified in the fifth patient. In addition to the overgrowth and learning difficulties, all five had a characteristic facial appearance and three had renal anomalies. The gestalt consists of a long, thin face with a prominent chin and nose. Renal anomalies included renal agenesis, horseshoe kidney, and hydronephrosis. We provide further support for a distinct "15q overgrowth syndrome" caused by either trisomy or tetrasomy resulting in increased dosage of distal 15q. In addition we propose that renal anomalies and a distinctive facial appearance be considered major features of this condition.

Minimizing discomfort during the injection of Radiesse with the use of either local anesthetic or ice.

Radiesse or calcium hydroxylapatite has been used for years in patients with HIV associated lipoatrophy as well as for facial wrinkles and nasolabial folds [2, 3], but can be painful to inject especially in the latter area. This discomfort can be severe enough that after an injection with Radiesse, a patient, despite excellent results, may refuse additional treatments. We hereby describe several methods of minimizing discomfort during Radiesse injections of nasolabial folds and other facial areas.

Oculoauriculovertebral spectrum phenotype caused by an unbalanced t(5;8)(p15.31;p23.1) rearrangement.

We present two siblings with oculoauriculovertebral spectrum phenotype (Goldenhar syndrome) and an unbalanced translocation t(5;8)(p15.31;p23.1) resulting in monosomy for the region 5p15.31 to 5pter and trisomy for 8p23.2 to 8pter region. The father was a carrier of the balanced rearrangement 46,XY,t(5;8)(p15.31;8p23.1). To our knowledge this is the first report of Goldenhar phenotype in association with an unbalanced (5p;8p) translocation.

Paternal inheritance of a 16qh-polymorphism in a patient with repeated IVF failure.

Polymorphisms of the size of heterochromatic centromeric regions of chromosomes have been well documented in the human. They appear to have no phenotypic effects in the carriers. However, they appear to be over-represented in infertile couples and those with repeated miscarriages, and there is now growing evidence that they are involved in meiotic pairing, spindle fibre attachment and chromosome movement. Here an analysis of inheritance is reported for a couple presenting with repeated IVF failure in which several embryos were identified as carriers of a polymorphism of the centromeric region of chromosome 16 (16qh-) following aneuploidy screening by sequential fluorescence in-situ hybridization (FISH), using probes for chromosomes 13, 16, 18, 21, 22, X and Y. Detailed cytogenetic analysis by high-resolution banding and FISH of both parents and grandparents established that the polymorphism was familial and inherited from the maternal grandfather. Furthermore, complete analysis of all embryonic nuclei from carrier embryos and others rejected for transfer because of aneuploidy revealed no abnormalities in the segregation pattern of chromosome 16.