Fraternal twins with Aarskog–Scott syndrome due to maternal germline mosaicism

Abstract

Aarskog-Scott syndrome is a rare X-linked recessive disorder with characteristic facial, skeletal, and genital abnormalities. We report on Aarskog-Scott syndrome in male dizygotic twins with an identical de novo mutation in FGD1 that resulted from germline mosaicism in the phenotypically normal mother. This is the first report of inheritance by germline mosaicism for the FGD1 gene.

Prenatal Diagnosis of Osteopathia Striata with Cranial Sclerosis in a Male Fetus with a ~330kb Deletion of Xq11.1 Involving the WTX Gene

“…Such mosaicism may result from one of two events: (1) in early embryogenesis a mutation occurs in a germ cell prior to meiosis and is carried in that cell's daughter cells or (2) a mutation occurs in a somatic cell prior to its separation into germ cells and is present in both somatic and germ cells. The timing of the mutation will ultimately determine the percentage of germ cells that carry the mutation, ranging from a few to 50% [8,9]. Using the Van der Meulen et al model for the recurrence risk for gonadal mosaics, the recurrence risk for this patient with three affected sons and two untyped unaffected daughters is 36.6% [10].…”

Somatic and germ‐line mosaicism of deletion 15q11.2–q13 in a mother of dyzigotic twins with Angelman syndrome

“…Germ line mosaicism has been postulated as a possible mechanism to explain the recurrence of various genetic diseases [Zlotogora, ; Gajecka et al, ; Tosca et al, ; Pilozzi‐Edmonds et al, ; Shanske et al, ; Slavin et al, ; Steinbusch et al, ]. AS deletion due to the presence of maternal germ line mosaicism, has only been described in two families.…”

Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015

“…These comprise 32 missense variants, 16 frameshift variants, 6 nonsense variants, 4 splice site variants, 1 in-frame deletion and 2 gross deletions. [2][3][4][5][6][7][8][9][10] In addition, a large duplication (exon 2-12) and a branch-point variant, both leading to a premature stop codon, have been described in affected families. 11,12 Germline mosaicism has been reported.…”

“…11,12 Germline mosaicism has been reported. 6 No definite genotype-phenotype correlation is apparent from comparison of patients with different variants; 2,10 however, affected members of one family with a c.1341G4A; p.(Trp447Ter) variant in exon 6 all presented with additional signs of myopathy and distal arthropathy. 8 …”

“…These approaches will facilitate the distinction of pathogenic variants from polymorphisms, especially in the cases of missense variants 1.8 Estimated frequency of the disease (incidence at birth ('birth prevalence') or population prevalence) Only 35 molecularly proven cases have been published worldwide. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] The majority of patients with a clinical diagnosis where details were published before the advent of molecular testing have not undergone subsequent molecular testing. Experience in Leuven (Prof. JP Fryns: personal communication), a typical-sized clinical genetics unit, suggests that two to three new patients with a proven variant in the FGD1 gene will be identified per year, a similar number as for Angelman and Prader-Willi syndrome.…”