FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?

• Published in: American journal of medical genetics. Part A Vol. 173; no. 12; pp. 3172 - 3181
• Main Authors: Myers, Angela, du Souich, Christèle, Yang, Connie L., Borovik, Lior, Mwenifumbo, Jill, Rupps, Rosemarie, Study, CAUSES, Lehman, Anna, Boerkoel, Cornelius F.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-12-2017
• Subjects: Amino Acid Sequence; Autism; Autism Spectrum Disorder - diagnostic imaging; Autism Spectrum Disorder - genetics; Carcinogenesis; cardiac hypertrophy; Cardiomyocytes; Congenital defects; Edema; Female; Foregut; Forkhead protein; Forkhead Transcription Factors - genetics; Foxp1 protein; Haploinsufficiency; Humans; Hyperplasia; Infant, Newborn; Intellectual disabilities; Intellectual Disability - diagnostic imaging; Intellectual Disability - genetics; Kidneys; Language Disorders - diagnostic imaging; Language Disorders - genetics; Lung - diagnostic imaging; Lung diseases; Lung Diseases - diagnosis; Lung Diseases - genetics; Lymphocytes; Male; Models, Molecular; Motor neurons; Mutation; neuro‐endocrine cell hyperplasia of infancy; periodic fever; Phenotype; Protein Domains; Repressor Proteins - genetics; Sequence Alignment; skeletal dysplasia; Skeleton; Speech; Stochasticity; Transcription factors; Urinary tract; Whole Exome Sequencing; neuro-endocrine cell hyperplasia of infancy; cardiac hypertrophy; periodic fever; skeletal dysplasia
• DOI: 10.1002/ajmg.a.38462
• EISSN: 1552-4833
• ISSN: 1552-4825

The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975‐2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing‐remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation.