TABLE 1.
Mutational and clinical details of females with BFLS due to variants in PHF6 and comparison to published males and female carriers
| Patient # | 1 | 2.1 (index) | 2.2 (mother) | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | female BFLS n = 27, 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 current study | male BFLS n = 62 2 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 | female carriers in XLR families n = 63 2 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 20 , 21 , 22 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PHF6 variant (NM_032458) | exon 6–7 deletion | c.88C>T, p.(Gln30*) | c.88C>T, p.(Gln30*) | c.129dup, p.(Lys44*) | c.346C>T, p.(Arg116*) | c.374+ 1G>A, r.spl | c.590_593del, p.(Asp197 Glyfs*20) | c.820C>T, p.(Arg274*) | c.845T>C, p.(Leu282 Pro) | c.859G>A, p.(Gly287 Ser) | c.898A>G, p.(Thr300Ala) |
19x truncating 5x missense |
7 families truncating 15 families missense |
NA |
| De novo | Yes | Maternal | Yes | Excl. In the mother | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 23/26 | 1/56 | 1/43 |
| Method | MLPA | Panel | Sanger segr. | Sanger | Panel | Exome | Sanger | Exome | Sanger | Exome | Trio exome | NA | NA | NA |
| skewed XI in blood | NA | XI 97.2 | XI 91.4 | XI 100 | XI 100 | XI 100 | XI 100 | NA | NA | XI 100 | NA | 22/22 (100%) | NA |
23/29 (79.3%) |
| Sex | Female | Female | Female | Female | Female | Female | Female | Female | Female | Female | Female | Female | Male | Female |
| Age | 4 y | 7 y 8 m | 36 y 2 m | 6 y 10 m | 10 y 10 m | 12 m | 12 m | 20 m | 15 y | 3 y | 12 y 7 m | several m to 41 y | 10 m to 62 y | NA |
| Body measurements | ||||||||||||||
| Gestational week | NA | 39 | term | 38 | NA | NA | NA | NA | 38 | 39 | NA | NA | NA | NA |
| Birth weight (g) | 4564 | 2850 | 2800 | 2950 | 3230 | 2300 | 2410 | 2140 | 2739 | 2644 | 3100 | NA | NA | NA |
| Birth length (cm) | NA | 49 | 50 | 49 | 49 | 47.5 | 49 | 44 | NA | 47 | 47 | NA | NA | NA |
| OFC at birth | NA | 36 | 34 | 36.5 | NA | 31 | 32 | 31.5 | NA | NA | 36.5 | NA | NA | NA |
| Weight (kg) / SD | NA | 22 / ‐0.58 | 88 / NA | 24.3 / 0.63 | 57.9 / 2.18 | 6.5 / ‐2.69 | 8.5 / ‐0.42 | 10.8 / 0.12 | NA | 12.1 / ‐1.82 | 67.7 / 2.01 | 2x under‐weight,15x normal, 5x obese | 2x underweight, 3x normal, 6x overweight | 14x normal, 4x obese |
| Height (cm) / SD | NA | 119 / ‐0.99 | 180 / 2.56 | 117.9 / ‐0.36 | 158.6 / 2.22 | 70.5 / ‐1.37 | 76 / 0.77 | 80 / ‐0.9 | NA | 92 / ‐2 | 161.2 / 0.98 | 2x short, 17x normal, 4x tall | 9x short, 12x normal | 2x short, 16x normal |
| OFC (cm) / SD | NA | 51 / ‐0.63 | NA | 51.9 / 0.38 | 53.3 / 0.26 | 43.5 / ‐1.86 | 46 / 0.3 | 45 / ‐2.25 | NA | 49 / ‐0.71 | 58.8 / 3.54 | 4x microcephaly, 14x normocephaly, 2x macrocephaly | 5x microcephaly, 25x normocephaly, 6x macrocephaly | 3x normal |
| Obesity | No | No | No | No | Yes | No | No | No | Yes | No | Yes |
5/25 (20%) |
44/48 (91.7%) |
4/19 (21.1%) |
| Characteristic facial gestalt | Yes | Yes | No (subtle) | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
23/25 (92%) typical female BFLS |
47/47 (100%) typical male BFLS |
16/23 (69.6%) subtle male BFLS |
| Development | ||||||||||||||
| Age at walking | 18 m |
Supported (7 y) |
10 m | 1 y 10 m | 15 m | Unsteady sitting (1 y) | NA |
Not yet (1 y 8 m) |
NA |
Sitting (2 y 2 m) not yet (3 y) |
1 y 1 m |
1 y to not yet at 7 y |
1 y 11 m to 4 y |
NA |
| First words | 2 y | No words | Normal | 3 y | 1 y 6 m | Not yet | Not yet | Not yet | No words | No words | 3 y 6 m | 15 m to not speaking | 4 y to not speaking | NA |
| Current speech ability | NA | Only vocalizations | Normal | 2–3 word sentences | Simple sentences | NA | NA | Hoarse voice | Growls | NA | Simple sentences | NA | NA | NA |
| Intellectual disability | Moderate | Severe/profound | No | Moderate | Mild/Moderate | Mild | Moderate | Severe | Severe | Moderate | Moderate |
24/27 (88.9%) |
54/54 (100%) |
6/32 (18.8%) learning disability |
| Neurological | ||||||||||||||
| Seizures | No | No | No | No | No | No | No | Yes | No | No | No | 5/23 | 3x | 2x |
| MRI anomalies | NA | Prominent outer cerebrospinal fluid space | NA | NA | Periventricular white matter lesions, frontal subcortical heterotopia | Small pituitary gland | NA | Delayed myelination, white matter loss, dysplastic pons, 3rd ventriculomegaly | NA | Abnormal position of the cerebellar tonsil | Normal MRI | 10/15 | NR | NR |
| Behavioral anomalies | No | Too impaired to assess | No | No | Earlier physically, now more verbally abusive | No | NA | Too impaired to assess | NA | Happy demeanor | Shy, anxious, friendly demeanor | 6/15 | 13/34 | 1x |
| Extremities | ||||||||||||||
| Finger anomalies | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | 24/25 (96%) |
16/16 (100%) reported as common in the rest |
8/21 (38.1%) |
| Clinodactyly | V | IV | IV | IV + V | No | IV + V | No | V | No | No | No | 16/25 (64.0%) | 5/16 (31.2%) | 0/21 (0%) |
| Brachydactyly | V | No | No | No | No | No | No | V | V | No | V | 13/25 (52.0%) | 3/16 (18.8%) | 0/21 (0%) |
| Camptodactyly | No | No | No | IV + V | Several fingers | No | No | No | No | No | No | 3/25 (12.0%) | 0/16 (0%) | 0/21 (0%) |
| Tapering fingers | No | No | No | No | Yes | No | No | No | No | Yes | Yes |
7/25 (28.0%) |
11/16 (68.8%) |
7/21 (33.3%) |
| Hypoplastic nails | No | No | No | No | No | No | Dysplastic, brittle | Hypoplastic V |
Hypoplastic V |
No | No |
8/25 (32.0%) |
2/16 (12.5%) |
1/21 (4.8%) |
| Toe anomalies | No | Yes, crowded toes | Yes, crowded toes | Yes, broad toes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
21/23 (91.3%) |
21/22 (95.5%) |
9/21 (42.8%) |
| Brachydactyly | No | No | No | No | No | No | No | Yes | No | No | IV + V |
5/23 (21.7%) |
12/22 (54.5%) |
8/21 (36.4%) |
| Camptodactyly/hammer toes | No | No | Yes | III, IV + V | II + III | No | No | No | No | No | No |
6/23 (43.5%) |
common in a sample of 25 22 | 0/21 (0%) |
| Sandal gap | No | No | No | No | No | No | No | No | No | No | Yes | 2/23 (8.7%) | 13/22 (59.1%) | 1/21 (4.8%) |
| Syndactyly | No | No | No | No | No | II‐IV right, II‐III left | Minimal II‐III | No | II‐III | II‐III | II‐III | 10/23 (43.5%) | 4/22 (18.2%) | 0/21 (0%) |
| Hypoplastic nails | No | Dysplastic v | Dysplastic v | No | No | No | Dysplastic, brittle | Hypoplastic | No | No | No | 7/23 (30.4%) | 1/22 (4.5%) | 1/21 (4.8%) |
| Other | ||||||||||||||
| Linear skin hyper‐pigmentation | No | Yes (both thighs) | No | No | Yes (groin + armpits) | No | Yes (legs) | No | Yes (arm + trunk) | Yes (trunk, bottom + legs) | No | 17/25 (68.0%) | NR |
0/1, NR |
| Dental anomalies | No | Small teeth, misalignment | Misalignment | Enamel defect | Hypodontia, large roots | NA | Small teeth | Hypodontia | NA | NA | Yes | 18/20 (90.0%) | 1x small teeth, widely spaced |
0/1, NR |
| Oligoamenorrhea (age at menarche) | NA | NA | yes (13 y) | NA | NA | NA | NA | NA | NA | NA | not yet | 10/10 (100%) | 44/45 (97.8%) hypogonadism or small external genitalia | 1/15 (6.7%) oligomenorrhea |
| Genital anomalies | No | Hypoplastic labia minora | No | No | No | No | No | No | Hypoplastic clitoris | No | NA | |||
| Eye anomalies | No | Strabism, hyperopia, excavation of the papilla | Myopia | Strabism, impaired stereo vision, astigmatism | Progressive retinal depigmentation, maculopathy | No | NA | No | No | NA | Nystagm, hyperopia, retinal depigmentation, maculopathy | Abnormalities in 13/15 | Abnormalities in 3/5 | NR |
| Other | No | Muscular hypotonia | No | Ectopic kidney, initially muscular hypotonia | Unilateral hydro‐nephrosis, congenital umbilical hernia, mild hearing impairment | Renal pilocalyceal dilatation | Hyertrichosis at the back | Cleft hard and soft palate, possible hearing impairment | No | Feeding difficulties | Muscular hypotonia | NA | NA | NA |
Abbreviations: II, III, IV, V, 2nd, 3rd, 4th, 5th finger or toe, respectively; m, months; NA, not available or not applicable; NR: not reported; XLR, x‐linked recessive (obligate female carriers with proven variant either in the female herself or in the family); XLR, X‐linked recessive; y, years, m, months; OFC, occipito‐frontal head circumference.