key: cord-0012575-1n34k3do
authors: Black, Holly A.; Parry, David; Atanur, Santosh S.; Ross, David; Rose, Elaine; Russell, Helen; Stock, Sarah; Warner, Jon; Porteous, Mary; Aitman, Timothy J.; Evans, Margaret J.
title: De novo mutations in autosomal recessive congenital malformations
date: 2016-06-09
journal: Genet Med
DOI: 10.1038/gim.2016.62
sha: 18a035017efaf725eb0c47c236b405cdbaca9736
doc_id: 12575
cord_uid: 1n34k3do

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resulting in a frameshift mutation and a premature stop codon (ENSP00000264895.6:p.Tyr3429Ter). Allele-specific polymerase chain reaction confirmed that the DNM had arisen on the paternal chromosome.

The variants were validated by Sanger sequencing, and the biological relationships within both trios were confirmed, showing that these were true DNMs. For these two fetuses, the clinical phenotypes were suggestive of autosomal recessive syndromes with a reported recurrence risk of 25%. In both cases, because one of the causative variants arose de novo, the recurrence risk is markedly reduced, with significant implications for future reproductive decisions. A small finite risk remains, however, owing to the possibility of germ-line mosaicism in the father in both families.

Three recently published trio-based exome sequencing studies, each including several thousand cases, a proportion of which presented as congenital malformations, did not report a single case of recessive disorder in which one of the causative alleles was a DNM. 1-3 Retterer et al. 1 reported exome sequencing in more than 3,000 cases and Yang et al. 2 in more than 2,000 cases; together these studies report more than 400 autosomal recessive molecular diagnoses, without a single case of a DNM contributing to the genetic etiology. The Deciphering Developmental Disorders project did not identify enrichment for any functional class of DNMs in autosomal recessive developmental disorder-linked genes. 3 Although our study size is small, it suggests that DNMs may have a more important role in autosomal recessive congenital malformation than has previously been considered.

Given that the identification of a causative DNM in recessive disease leads to a low predicted recurrence risk but has hitherto been infrequently reported, we recommend that the frequency of this mode of inheritance be analyzed systematically in a larger series of cases, particularly in patients presenting with a congenital malformation. Future studies of recessive disease should specifically report whether this mechanism contributes to any of their cases. For accurate clinical reporting, this mode of inheritance should always be considered a possible contributor to the cause of autosomal recessive congenital malformation. Clinical confirmation of parental carrier status will help to ensure accurate reporting of recurrence risk in autosomal recessive disease. 

Tommy's Centre for Maternal and Fetal Health

Clinical application of whole-exome sequencing across clinical indications

Molecular findings among patients referred for clinical whole-exome sequencing

Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders