Severe microcephaly

Gene: FTO

I don't know

There are now 5 unrelated probands reported in literature with homozygous FTO missense variants and a syndromic presentation of growth retardation, developmental delay, facial dysmorphism, and multiple congenital anomalies. Microcephaly was present in 4/5 probands, but the severity was borderline (at <3rd or <2nd percentile). Hence, this gene can only be rated Amber on the Severe microcephaly panel.

Created: 26 Oct 2026, 10:48 a.m. | Last Modified: 26 Oct 2026, 10:48 a.m.

Panel Version: 9.44

PMID: 37529081 Mayman et al., 2023
Case report: female proband homozygous for FTO c.287G>C, p.Arg96Pro.16 months old at time of report. She had numerous abnormalities across multiple organ systems, affecting respiratory, cardiovascular, and neurological function, including severe developmental delay. Fetally detected anomalies included polyhydramnios, IUGR (estimated fetal weight <1%), brain anomalies (poor gyral development, small cerebral hemispheres, and Dandy-Walker spectrum anomaly with incompletely rotated vermis, large foramen of Magendie, large cisterna magna, and hydrocephalus), musculoskeletal anomalies (all long bones <5% mean for gestational age without evidence of fracture, thoracic cage 9% mean for gestational age, and disorganized anterior maxillary tooth buds), and cardiovascular (ventricular septal defect, hypoplastic mitral valve, and aortic arch). No microcephaly.

PMID: 26697951 Rohena et al., 2016
Report of a homozygous FTO c.965G>A, p.R322Q variant associated with a lethal malformation syndrome in a consanguineous Yemeni family. The 2 affected sibs (male and female) presented with poor growth, microcephaly (<3rd percentile), and cardiac anomalies. Cranial CT of proband A showed severe ventriculomegaly and cerebral atrophy. He also had profound GDD, craniosynostosis, bilateral cataracts, cryptorchidism, micrognathia, and other annomalies.
Proband B, his younger sister, had dysmorphic facial features, clinodactyly, mild clubfeet, and truncal hypotonia with mild spasticity. Both individuals died due to respiratory failure, at 6 and 2.5 years old.
Exome seq also detected a homozygous VUS TRIM37 variant in proband B (TRIM37 is associated with AR growth disorder with prenatal onset, including occasional progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms tumor - authors note these characteristic features were not present in the siblings).

PMID: 26740239 Çağlayan et al., 2016
Report of a female patient with a homozygous missense mutation in FTO (c.812A>C, p.His271Pro) and a homozygous nonsense mutation p.Arg403X in CETP. No CNVs. Method: WES. CETP is associated with AD Hyperalphalipoproteinemia in OMIM (143470). Parents are second cousins.
Proband presented with microcephaly (head circumference was 41 cm (<2nd percentile) and 9 months old and 47cm (<3rd percentile) at 5 yrs 5 mo), developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia, bilateral hearing loss, and other various phenotypic abnormalities. She had low LDL cholesterol and high HDL cholesterol; diagnosed with CETP-related hyperalphalipoproteinemia.
Western blot analysis demonstrated no changes in patient FTO. Q-PCR analysis revealed slightly decreased levels of FTO expression in patient cells compared to controls.

PMID: 26378117 Daoud et al., 2016
Report of a 21-month-old female with growth retardation and developmental delay, harbouring a homozygous mutation in FTO: p.(Arg316Gln). She presented with distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. Microcephaly was borderline severe (at the 2nd centile). Seq method: Targeted NGS panels of 4000+ genes.

PMID: 19559399 Boissel et al. 2009
Report of a consanguineous Palestinian Arab family in which 9 individuals had a severe multiple congenital anomaly syndrome with death by age 3 years. Clinical features dysmorphic facial features, retrognathia, severe failure to thrive in infancy, IUGR (3/9), heart defects (6/9: VSD, AVD, PDA, 4 had hypertrophic cardiomyopathy), severe developmental delay (9/9), microcephaly, lissencephaly, seizures, Dandy-Walker malformation, and other more variable features. Affected individuals were homozygous for FTO:c.947G>A, p.Arg316Gln. Method: autozygosity mapping + targeted analysis of 28 genes on chromosome 16q12.

FTO is associated with AR Growth retardation, developmental delay, facial dysmorphism, OMIM:612938 (OMIM accessed 23rd Oct 2026).
Sources: Literature

Created: 26 Oct 2026, 10:44 a.m. | Last Modified: 26 Oct 2026, 10:46 a.m.

Panel Version: 9.44

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Growth retardation, developmental delay, facial dysmorphism, OMIM:612938; lethal polymalformative syndrome, Boissel type, MONDO:0013050

Publications

• 19559399
• 26378117
• 26740239
• 26697951
• 37529081

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments