BPTF – Neurodevelopmental Disorder with Dysmorphic Facies and Distal Limb Anomalies

Heterozygous loss-of-function variants in the BPTF gene cause an autosomal dominant neurodevelopmental disorder characterized by developmental delay, intellectual disability, dysmorphic facies, and distal limb anomalies (neurodevelopmental disorder with dysmorphic facies and distal limb anomalies).

Initial reports described 11 individuals with de novo BPTF variants, including eight loss-of-function and two missense changes, presenting with developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features (PMID:28942966).

A cohort of 25 novel individuals harboring 20 distinct BPTF variants, four of which were inherited, expanded the phenotypic spectrum to include seizures and scoliosis (PMID:33522091). Two additional Chinese probands with c.1133G>A (p.Arg378Gln) variant exhibited short stature and benefited from growth hormone therapy (PMID:36153657). A recent study reported four severe cases with splice (c.2812+1G>C) and missense (c.6022G>A, c.6416G>A) variants, correlating distal limb anomalies with more profound intellectual disability (PMID:40415676).

All reported cases follow an autosomal dominant inheritance pattern with evidence of segregation in four families (PMID:33522091).

Variants span the spectrum of haploinsufficiency alleles, including nonsense (e.g., c.4177C>T (p.Arg1393Ter)), frameshift, splice-site, and missense changes consistent with loss of BPTF function.

Functional studies in zebrafish using CRISPR-Cas9 bptf knockouts recapitulate human phenotypes, showing reduced head size, increased neural apoptosis, and craniofacial anomalies, supporting a haploinsufficiency mechanism (PMID:28942966).

Integration of extensive de novo and inherited cases with concordant in vivo modeling establishes a robust gene–disease relationship. Key Take-home: BPTF haploinsufficiency is a clinically actionable cause of a syndromic neurodevelopmental disorder, guiding genetic testing and management.

References

• American journal of human genetics • 2017 • Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features PMID:28942966
• American journal of medical genetics. Part A • 2021 • Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies PMID:33522091
• Molecular genetics & genomic medicine • 2023 • The effect of growth hormone treatment in children with novel BPTF gene variants: A report of two cases and literature review PMID:36153657
• Developmental neurobiology • 2025 • Effects of the Missense Variants on Complete Phenotype and Splicing Variant on Severe Growth Retardation in the BPTF Gene PMID:40415676

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