Inherited surfactant deficiency caused by uniparental disomy of rare mutations in the surfactant protein-B and ATP binding cassette, subfamily a, member 3 genes.
OBJECTIVE
To characterize inheritance of homozygous, rare, recessive loss-of-function mutations in surfactant protein-B (SFTPB) or ATP binding cassette, subfamily A, member 3 (ABCA3) genes in newborns with lethal respiratory failure.


METHODS
We resequenced genes from parents whose infants were homozygous for mutations in SFTPB or ABCA3. For infants with only 1 heterozygous parent, we performed microsatellite analysis for chromosomes 2 (SFTPB) and 16 (ABCA3).


RESULTS
We identified 1 infant homozygous for the g.1549C > GAA mutation (121ins2) in SFTPB for whom only the mother was heterozygous and 3 infants homozygous for mutations in ABCA3 (p.K914R, p.P147L, and c.806_7insGCT) for whom only the fathers were heterozygous. For the SP-B-deficient infant, microsatellite markers confirmed maternal heterodisomy with segmental isodisomy. Microsatellite analysis confirmed paternal isodisomy for the 3 ABCA3-deficient infants. Two ABCA3-deficient infants underwent lung transplantation at 3 and 5 months of age, respectively, and 2 infants died. None exhibited any nonpulmonary phenotype.


CONCLUSIONS
Uniparental disomy should be suspected in infants with rare homozygous mutations in SFTPB or ABCA3. Confirmation of parental carrier status is important to provide recurrence risk and to monitor expression of other phenotypes that may emerge through reduction to homozygosity of recessive alleles.
Hamvas
Aaron
A
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, MO 63110, USA. hamvas@kids.wustl.edu
Nogee
Lawrence M
LM
Wegner
Daniel J
DJ
Depass
Kelcey
K
Christodoulou
John
J
Bennetts
Bruce
B
McQuade
Leon R
LR
Gray
Peter H
PH
Deterding
Robin R
RR
Carroll
Travis R
TR
Kammesheidt
Anja
A
Kasch
Laura M
LM
Kulkarni
Shashikant
S
Cole
F Sessions
FS
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D037701:Pulmonary Surfactant-Associated Protein B / Q000172:deficiency* / Q000235:genetics*; D024182:Uniparental Disomy / Q000175:diagnosis* / Q000235:genetics*
C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D037701:Pulmonary Surfactant-Associated Protein B