RARB – Matthew-Wood syndrome

Matthew-Wood syndrome (PDAC syndrome; MONDO:0011010) is characterized by anophthalmia/microphthalmia, pulmonary hypoplasia, congenital diaphragmatic hernia, and cardiac defects in the neonatal period.

RARB encodes retinoic acid receptor-beta, a ligand-activated transcription factor critical for ocular and organogenesis signaling (RARB; Matthew-Wood syndrome).

Genetic evidence supports both autosomal recessive and autosomal dominant inheritance. Two siblings were compound heterozygous for a nonsense and a frameshift variant segregating with disease, and three unrelated probands harbored de novo missense alterations affecting Arg387, indicating gain-of-function (PMID:24075189).

Variant spectrum includes bi-allelic loss-of-function alleles (c.355C>T (p.Arg119Ter), c.1205_1206dup (p.Ile403SerfsTer15)) and de novo missense gain-of-function alleles (c.1159C>T (p.Arg387Cys), c.1159C>A (p.Arg387Ser)).

Functional assays demonstrate that p.Arg119Ter and p.Ile403SerfsTer15 abolish ligand-induced transcriptional activity, while p.Arg387Cys/Ser confer a 2- to 3-fold increase in retinoic acid responsiveness, supporting a dual loss- and gain-of-function mechanism (PMID:24075189).

Collectively, moderate clinical validity is supported by five probands (two recessive, three de novo), segregation in a recessive family, and concordant functional data. Key take-home: RARB sequencing should be included in diagnostic panels for PDAC syndrome given clear implications for prognosis and genetic counseling.

References

• American journal of human genetics • 2013 • Recessive and dominant mutations in retinoic acid receptor beta in cases with microphthalmia and diaphragmatic hernia. PMID:24075189

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