Table 1.
Summary of PHF6 mutations in BFLS patients in different individuals from different families. Classical features of BFLS includes mild to severe mental retardation, hypogonadism, hypometabolism, obesity with marked gynecomastia, facial dysmorphism, narrow palpebral fissure, large and fleshy ears, tapered fingers.
| F/M | Nucleotide | Amino Acid | Mutation | Reported clinical features | Behavioral disturbances | Ref |
|---|---|---|---|---|---|---|
| M | c. 2T>C | p.M1T | Missense | Classical features of BFLS with no detailed clinical records. | N/A | (Lower et al., 2002) |
| M | c. 2T>C | p.M1T | Missense | Classical features of BFLS. Born at term after uneventful pregnancy, delayed early milestones, walked at age 4, began saying a few words at age 5, height of 140cm (<3rd centile), weight of 45kg (5th centile), and occipital-frontal head circumference of 53.3cm (10th-25th centile) at age 15, short stature, triangular face, hyperplastic supraorbital digits, deep-set eyes, large ears, gynecomastia, lower abdominal obesity, and small penis and testes with no evidence of pubertal change. |
N/A | (Crawford et al., 2006) |
| M | c.134G>A | p.C45Y (familial) | Missense | Classical features of BFLS with no detailed clinical records. | N/A | (Lower et al., 2002) |
| M | c.134G>A | p.C45Y (de novo) | Missense | Classical features of BFLS with no detailed clinical records. | N/A | (Lower et al., 2002) |
| M | c.266G>T | p.G89Y | Missense | Classical features of BFLS. At age 22, height 173cm, weight 108kg, head circumference 61cm. Moderate intellectual disability; delayed development, no epileptic seizures. Brother has similar symptoms with severe intellectual disability, Female carrier in the family has shown mild intellectual disability. |
Good tempered with occasional aggressive attacks | (Mangelsdorf et al., 2009) |
| M | c.296G>T | p.C99F | Missense | Classical features of BFLS. Female carrier has mild clinical features of BFLS including obesity, large ears, amenorrhea, hypothyroidism, epilepsy, and learning difficulties. |
N/A | (Lower et al., 2002) |
| M,F | c.686A>G | p.H229R | Missense | Classical features of BFLS with no detailed clinical records. | N/A | (Lower et al., 2002) |
| M | c.700A>G | p.K234E | Missense | Classical features of BFLS with no detailed clinical records. | N/A | (Lower et al., 2002) |
| M | c.769A>G | p.R257G | Missense | Classical features of BFLS with no detailed clinical records. | N/A | (Lower et al., 2002) |
| M | c.769A>G | p.R257G | Missense | Classical features of BFLS. Severe intellectual disability, self-injurious behavior, stooped hyposcoliotic posture, central obesity, marked gynecomastia, hypogonadism, and hand and feet anomalies. Hodgkin’s lymphoma |
N/A | (Vallée et al., 2004) (Carter et al., 2009) |
| M | c.940A>G | p.I314V | Missense | Classical features of BFLS. Psychomotor developmental delay, language delay, mild intellectual disability (IQ of 61). At age 18, height 171.5 cm, head circumference 55.7cm, moderate obesity, marked gynecomastia. |
Lack of inhibition in sexual contact; limbs showing hypermobility. | (Crawford et al., 2006) |
| M | c.22A>T | p.K8X | Nonsense | Classical features of BFLS. | (Lower et al., 2002) | |
| F | c.955C>T | p.R319X | Nonsense | Classical features of BFLS. Head circumference 34cm (−0.5SD), delayed walking at age 2.5. During first years, frontotemporal alopecia, nystagmus, strabismus, small teeth, hypoplastic labia minora and clitoris. At age 6, head circumference of 49cm (−1.63SD), moderate to severe intellectual disability, facial dimorphism, and tapering fingers. Normal MRI. |
Lack of swallowing coordination; Sociable and happy | (Zweier et al., 2013) |
| M | c.1024C>T (original family) | p.R342X | Nonsense | Classical features of BFLS. Developmental delay, upslanting palpebral fissures, large ears, a high palate, hypotonia, cryptorchidism, and an inguinal hernia. At age 15, talk sentances consisting of three or four words, short stature and obesity, large ears, protruding cheeks,. Female carrier has normal cognitive function. Big hands, ears and feet, with some sensory impairment in the legs. Normal MRI. |
Female carrier is clumsy when running or jumping. | (Gécz, Turner, Nelson, & Partington, 2006; Lower et al., 2004) |
| M | c.1024C>T | p.R342X | Nonsense | Delayed developmental milestones, height on 25th centile, weight over 97th centile, head circumference over 98th centile, narrow bitemporal diameter, upslanting eyes, prominent supraorbiral ridges, hypotelorism, long ears/earlobes, a prominent chin, obese, marked gynecomastia, a hypoplastic scrotum with retractile testes, cubitus valgus, tapered fingers. Female carrier is obese, has deep-set eyes, prominent supraorbital ridges, large ear lobes, tapered fingers, broad feet and short toes. |
N/A | (Lower et al., 2002) |
| M | c.1024C>T | p.R342X | Nonsense | Classical features of BFLS. | N/A | (Lower et al., 2002) |
| M | c.1024C>T | p.R342X | Nonsense | Classical features of BFLS. | N/A | (Crawford et al., 2006) |
| M | c.1024C>T | p.R342X | Nonsense | Classical features of BFLS. | N/A | (Crawford et al., 2006) |
| M | c.1024C>T | p.R342X | Nonsense | Classical features of BFLS and T cell acute lymphoblastic leukemia at age 9 | N/A | (Chao et al., 2010) |
| F | c.27dupA | p.G10fsX21 | Frameshift | Classical features of BFLS. Delayed speech, normal IQ of 87, high level of thyroid stimulating hormone, low level of thyroxin at age 7–8; at age 14, height 180cm, weight 115 kg, shallow forehead, fleshy earlobes, deep set eyes, broad feet, hammertoes, no menstruation at age 14. |
Poor coordination; Tactile defensive and emotionally labile, poor spatial awareness, and startles to noise |
(Crawford et al., 2006) |
| M | IVS2-8A>G | M46fsD exon3 | Frameshift | Classical features of BFLS with mild to moderate intellectual disability, and global developmental delay. | N/A | (Vallée et al., 2004) |
| F | c.677delG | p. G226fsE53 | Frameshift | Classical features of BFLS Diagnosed with Coffin Siris Syndrome in early infancy. At 9 years old, height 1.7SD, weight 30kg, head circumference 54cm (1.4SD). Mild intellectual disability, mild clinodactyly, short toes, and facial dysmorphism. |
Shy and intolerance for being alone; anxiety; sleeping difficulties | (Wieczorek et al., 2013; Zweier et al., 2013) |
| F | c.914G>T | p. C305F | Missense | Classical features of BFLS, previously diagnosed with Coffin Siris Syndrome, unstable gait on stairs, head circumference of −1.0SD at age 11, susceptibility to urinary tract infections, frequent constipation, facial dysmorphism, and tapered fingers. | Aggressive behavior | (Wieczorek et al., 2013; Zweier et al., 2013) |
| F | Dosage gain of exon 4, 5 | Duplication | Classical features of BFLS, delayed milestones, delayed speech, conductive hearing loss, potential retinal dystrophy, and seizures at age 20. At age 22, head circumference 56.5(1.4 SD), facial dysmorphism, tapering fingers. | Unstable gait; behavioral problems including short attention span, hyperactivity, compulsive behavior, sleeping difficulties, and lack of emotional detachment. | (Zweier et al., 2013) | |
| F | Dosage gain of exon 4, 5 | Duplication | Classical features of BFLS. Head circumference of 34cm (1.4 SD) at birth; At age 3–4 month, several single seizures, delayed walking and language, constipation, and neurogenic bladder. At age 32, head circumference 54cm (−0.3 SD). |
Sociable behavior | (Zweier et al., 2013) | |
| F | 6kb deletion | Affecting exon 4, 5 | Deletion | Classical features of BFLS with moderate intellectual disability. Head circumference 53cm (2.2SD), linear skin hyperpigmentation, and facial dimorphism. | Sociable behavior, | (Zweier et al., 2013) |
| F | 100kb deletion | Deletion of last 5 coding exons | Deletion | Classical features of BFLS. Delayed developmental milestone, feeding difficulties, muscular hypotonia, single horseshoe kidney, obstructive uropathy, recurrent pyelonephritis, and multiple febrile seizures. | N/A | (Di Donato et al., 2014) |
| F | 15kb deletion | Deletion of last 3 exons | Deletion | Classical features of BFLS with mild intellectual disability. At age 7, mild hearing loss, and recurrent middle ear infections; At age 16, head circumference 56.6cm (75th centile), slightly widened ventricles and increased white matter signal abnormality on MRI. | N/A | (Berland et al., 2011) |
| M | c.999-1001 delTGA | p.D333del | Deletion | Classical features of BFLS with delayed milestones. | N/A | (Baumstark et al., 2003) |
| M | c.999-1001 delTGA | p.D333del | Deletion | First patient description. Delayed milestones, severe mental deficiency with IQ of 20, seizures, large ears, short stature, small genitalia, and small pituitary gland. Coarse gyri, widened ventricular system, cortical dysplasia with indistinct lamination, and heterotopias. |
Hyperactive and aggressive behaviors | (Börjeson, Forssman, & Lehmann, 1962; Gécz et al., 2006) |
| F | Entire gene deleted | Deletion | Classical features of BFLS. Head circumference 35.5 (0.5SD) at birth, delayed motor milestones and facial dysmorphism. muscular hypotonia, ectopic left kidney, strabismus, hyperopia, bilateral sensorineural hearing loss, enlarged ventricles on MRI. | Compulsive eating behavior; Severe sleeping difficulties, | (Zweier et al., 2013) | |
| F | 270kb deletion | Deletion | Classical features of BFLS. Mild muscular hypotonia, mild speech delay, narrow external auditory canal, mild learning disability; IQ within borderline to normal range. | N/A | (Di Donato et al., 2014) |