Somatic mosaicism in a mother of two children with Pitt–Hopkins syndrome

Abstract

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, unusual face and breathing abnormalities and can be caused by haploinsufficiency of TCF4. The majority of cases are sporadic. Somatic mosaicism was reported infrequently. We report on a proband with typical manifestations of PTHS and his younger brother with a less striking phenotype. In both, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4. The same mutation was found at low levels in DNA extracted from the mother's blood, urine and saliva. This report of familial recurrence with somatic mosaicism in a healthy mother has important consequences for genetic counseling. We suggest careful studies in parents of other patients with PTHS to determine the frequency of germline and somatic mosaicism for TCF4 mutations.

Diagnosis and management in Pitt‐Hopkins syndrome: First international consensus statement

“…Recurrence risk for sibs of affected individuals is therefore generally low. Germ line or low‐grade parental mosaicism has been reported in four instances, representing 2% to 3% of published cases . Additionally, our joint experience in 273 individuals with molecularly confirmed PTHS indicates five recurrences in siblings without a detectable (mosaic) TCF4 variant in the parents.…”

“…Germ line or low-grade parental mosaicism has been reported in four instances, representing 2% to 3% of published cases. 15,22,42,43 Additionally, our joint experience in 273 individuals with molecularly confirmed PTHS indicates five recurrences in siblings without a detectable (mosaic) TCF4 variant in the parents. Therefore, we confirm an empiric recurrence risk of up to 2% (R4).…”

Pitt–Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription

“…Although the majority of cases of PTHS arise as a result of sporadic, spontaneous mutations in the TCF4 gene, Steinbusch et al 43 have reported somatic mosaicism of the TCF4 gene in a mother with two children manifesting PTHS. In both children, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4: the same mutation was found at low levels in DNA from the mother.…”

“…In both children, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4: the same mutation was found at low levels in DNA from the mother. As Steinbusch et al 43 suggest, the possibility of familial recurrence with somatic mosaicism in a healthy mother has important consequences for genetic counseling of PTHS families. This consideration may also explain an early report of possible PTHS in two siblings, 28 although an alternative explanation could be the more recently characterized possibility of manifestation of a PTHS-like ID disorder manifesting autosomal recessive inheritance through NRXN1 and CNTNAP2 mutations, as will be described in the next paragraph.…”

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

“…De novo mutations, germline mosaicism and other complexities Although this concept of somatic mosaicism has been in the literature for many years [131][132][133][134][135], it is really only recently that more people are beginning to realize that it might be much more extensive in humans than previously thought [23,[136][137][138][139][140][141][142][143][144][145][146][147][148][149]. In fact, hardly anything is truly known regarding the extent of somatic mosaicism in humans and its effect on phenotype in even well studied diseases.…”