Alveolar capillary dysplasia with misalignment of pulmonary veins

Gene: LINC01081

Green List (high evidence)

Comment on list classification: There are at least 3 reported unrelated individuals with Alveolar capillary dysplasia with misalignment of pulmonary veins, where LINC01081 (either part or whole gene) has been deleted (PMID: 27071622, 23034409). At least 10 other patients harboured a deletion that affected the FOXF1 upstream enhancer region, but not FOXF1 itself (PMIDs: 19500772; 23034409; 24842713; 27071622). Hence, the testing region should be expanded to include the enhancer.
The majority of CNVs arose de novo on the maternal allele - suspected imprinting of paternal allele.
Based on the available evidence, this gene should be rated GREEN for Alveolar capillary dysplasia with misalignment of pulmonary veins.

Created: 15 Oct 2025, 12:46 p.m. | Last Modified: 15 Oct 2025, 1:27 p.m.

Panel Version: 1.2

As reviewed by Hannah Robinson, LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer region of FOXF1. Like FOXF1, genes in the enhancer region have been implicated in Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Aside from ACDMPV, cardiac, gastrointestinal and genitourinary phenotypes are also common.

Most CNVs are de novo, arising on the maternal allele - suspected imprinting of paternal allele. According to PMID:36157490 Szafranski et al., 2022, 50 reported de novo CNV deletions arose on the maternal chromosome 16 and only 3 de novo CNV deletions arose on the paternal chromosome 16.

PMID: 27071622 Szafranski et al., 2016
22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. In seven cases (patients 117.3, 119.3, 122.3, 126.3, 127.3, 136.3, and 139.3) the deletion CNVs affected only the upstream enhancer, leaving FOXF1 intact.

Genomic positions reference (GRh37/hg19):
FOXF1 (ENST00000262426.6_4) - chr16:86,544,133-86,549,028.
LINC01081 (ENST00000806422.1_2) - chr16:86,255,967-86,338,313
LINC01082 (ENST00000806580.1_1) - chr16:86,184,957-86,192,637

Enhancer only deletions, from supplementary information:
P122.3: 4.1 kb deletion (86,216,561-86,220,676), mapping ~ 9.1 kb upstream to LINC01082 (intergenic) - paternal origin
P117.3: 233kb deletion (86,055,159/200-86,288,226/267) - both genes affected
P119.3: 153kb deletion (86,148,250- 86,301,591) + Insertion at the break point: GCACGCA - both genes affected
p126.3: 1511kb deletion (84,875,483/490-86,386,861/868) - both genes affected, multiple other genes deleted; additional phenotypes: balanced AVSD, Intestinal malrotation, Uterus didelphys, Mildly dilated right ureter
P127.3: 92kb deletion (86,209,157/194-86,301,558/595) - LINC01081 only; additional cardiac phenotype: Patent ductus arteriosus and patent foramen ovale
P136.3: 1250kb deletion (~85,146,556-86,393,283) - both genes affected, multiple other genes deleted
P139.3: 405KB deletion (~85,877,026-86,282,104)- both genes affected, IRF8 also deleted.

PMID: 19500772 Stankiewicz et al. (2009)
P28.7 (D10): 145kb deletion ~86,140,499-86,285,499 - both genes affected; additional cardiac phenotype: Patent ductus arteriosus
P47.4 (D9): 524kb deletion 85,867,768-86,392,161 - both genes deleted, as well as IRF8; additional phenotypes: Suspected intestinal malrotation, imperforate anus; Bicornuate uterus with cervical duplication; Multiple butterfly vertebrae.

PMID: 23034409 Szafranski et al. (2013a)
Further 7 cases with enhancer deletions (5 where both genes are affected, 2 cases with only LINC01081 deleted).
P77.3: deletion of chr16:86,212,041/067-86,448,132/158 - only LINC01081 deleted
P81.3: deletion of chr16:86,194,972/195,808 - 86,354,712/355,161 - only LINC01081 deleted

PMID: 24842713 Szafranski et al. (2014)
P99.3: deletion of chr16:84,764,628/647 - 86,238,601/620 - only LINC01082 affected (and additional genes deleted upstream)
P111.3: deletion of chr16:86,077,955/958 - 86,271,915/918 - both genes affected; additional cardiac phenotype: PDA, dilated right ventricle with depressed function

This gene is not yet linked to any disease in OMIM (accessed 15th Oct 2025).

Created: 15 Oct 2025, 10:08 a.m. | Last Modified: 15 Oct 2025, 1:06 p.m.

Panel Version: 1.2

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Alveolar capillary dysplasia with misalignment of pulmonary veins

Publications

• 19500772
• 23034409
• 24842713
• 27071622

Green List (high evidence)

LINC01081 and LINC01082 are long non-coding RNA genes within a known upstream enhancer of FOXF1. Pathogenic variants in FOXF1 or deletions of its upstream enhancer region cause alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) (MIM265380). The majority of previously reported deletions of the upstream enhancer region have occurred de novo on the maternal allele.
Sources: NHS GMS

Created: 8 Aug 2025, 11:42 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Alveolar capillary dysplasia with misalignment of pulmonary veins

Publications

• PMID: 27071622
• PMID: 27822317

Variants in this GENE are reported as part of current diagnostic practice