- OMIM ID: 146510
- OMIM diseaseName: #146510 PALLISTER-HALL SYNDROME; PHS
;;HYPOTHALAMIC HAMARTOBLASTOMA, HYPOPITUITARISM, IMPERFORATE ANUS, AND
- OMIM diseaseClinical_Synopsis: INHERITANCE:
Intrauterine growth retardation
HEAD AND NECK:
Absent external auditory canals;
Posteriorly rotated ears;
Flat nasal bridge;
Multiple buccal frenula;
Cleft lip and palate;
Ventricular septal defect;
Proximal aortic coarctation;
Patent ductus arteriosus
Bifid or hypoplastic epiglottis;
Abnormal lung lobation
[Ribs, sternum, clavicles, and scapulae];
[External genitalia, male];
Distal shortening of limbs;
Short 4th metacarpals;
SKIN, NAILS, HAIR:
Midline facial capillary hemangioma;
[Central nervous system];
Pituitary aplasia or dysplasia
Adrenal gland hypoplasia;
Most cases sporadic;
Long-term survivors require hormone replacement
Caused by mutations in the GLI-Kruppel family member 3 gene (GLI3,
- OMIM diseaseText: A number sign (#) is used with this entry because of evidence that
Pallister-Hall syndrome is caused by heterozygous mutation in the GLI3
gene (165240) on chromosome 7p14.
Pallister-Hall syndrome is a pleiotropic autosomal dominant disorder
comprising hypothalamic hamartoma, pituitary dysfunction, central
polydactyly, and visceral malformations (Biesecker et al., 1996).
Hall et al. (1980) reported 6 infants with a neonatally lethal
malformation syndrome of hypothalamic hamartoblastoma, postaxial
polydactyly, and imperforate anus. Some had laryngeal cleft, abnormal
lung lobation, renal agenesis or dysplasia, short fourth metacarpals,
nail dysplasia, multiple buccal frenula, hypoadrenalism, microphallus,
congenital heart defect, and intrauterine growth retardation. All cases
were sporadic and chromosomes were apparently normal. The parents were
nonconsanguineous. No environmental exposure was common to all cases.
The ages of the fathers were 21, 25, 25, 29, 43, and unknown. The
anterior pituitary was not found in any patient. The hypothalamic tumor
was apparent on the inferior surface of the cerebrum and extended from
the optic chiasma to the interpeduncular fossa. The tumor replaced the
hypothalamus and other nuclei that originate in the embryonic
hypothalamic plate. It was composed mainly of cells resembling
primitive, undifferentiated germinal cells.
Graham et al. (1983) described an infant with abnormal auricles, short
nose with flattened bridge, microglossia, micrognathia, cleft palate,
short limbs, dislocated hips, and 4-limb postaxial polydactyly. The
infant died at 2 hours of age and autopsy showed hypothalamic
hamartoblastoma. A sister of the mother died at 17 hours of age and
showed 4-limb polydactyly, recessed mandible, and small tongue; autopsy
was not done. See 241800.
Iafolla et al. (1989) reported that nail dysplasia accompanies the
Pallister et al. (1989) described 3 additional cases. One patient had
imperforate anus and right hydronephrosis and hydroureter with absent
left kidney; another had imperforate anus without the renal anomalies. A
teratogen had been suspected because of the fact that cases were not
recognized before February 1978. Pallister et al. (1989) suggested,
however, that autopsy of cases of imperforate anus with associated CNS
lesions should be reviewed.
Finnigan et al. (1991) described 2 unrelated patients with the usual
features of Pallister-Hall syndrome, including diencephalic anomalies,
but without hamartoblastomas.
Topf et al. (1993) reported affected father and son. The 9-year-old son
had precocious puberty, imperforate anus, postaxial polydactyly,
hypospadias, a hypothalamic mass, and a displaced pituitary gland; his
34-year-old father had polydactyly, a hypothalamic mass, and a flattened
pituitary gland. In the son imperforate anus, postaxial polydactyly, and
hypospadias, were surgically corrected early in life. His subsequent
growth and development were normal. He had minor craniofacial
dysmorphism. At the age of 8 years, he presented because of precocious
puberty and was found by MRI scan to have a large hypothalamic mass and
displaced pituitary. The father's polydactyly consisted of an accessory
digit, apparently originating from the third metacarpal. His facial
features resembled those of the son. He did not have a history of
imperforate anus or hypospadias.
Penman Splitt et al. (1994) also reported an instance of male-to-male
transmission: a 9-year-old boy had hamartoblastoma, midaxial and
postaxial polydactyly with brachydactyly, hypospadias, imperforate anus,
and precocious puberty. The 34-year-old father had central and postaxial
polydactyly, macrocephaly, and a hypothalamic mass. Both were of normal
Thomas et al. (1994) reported a definite sib recurrence of
Pallister-Hall syndrome in a family without a cytogenetically visible
chromosome abnormality. The father of the 2 affected sibs was born with
nearly identical digital abnormalities and could represent either mild
expression or mosaicism for a dominant gene. The first-born infant, a
female, was noted at birth to have choanal atresia, bifid epiglottis,
and cleft upper larynx with posterior web in the subglottic area. Her
nose was short, with depressed nasal bridge and anteverted nares. There
was bilateral hexadactyly with osseous 2/3 syndactyly of the right hand
that was thought to represent an insertional type of polydactyly.
Subsequently she developed signs of hypopituitarism, had recurrent
problems with upper airway obstruction eventually necessitating
tracheostomy, and required gastrostomy because of feeding difficulties.
She died at 12 months of age after a respiratory infection. At necropsy,
a tracheal diverticulum and abnormal lobation of the lungs were found.
The pituitary gland was absent with a rudimentary stalk. A 2 x 2 cm soft
nodular mass completely replaced the hypothalamus. The male sib was born
at 30 weeks' gestation and required respiratory support after birth for
upper airway obstruction. He had 4/5 syndactyly of the right hand with
postaxial polydactyly of both hands and short fourth and fifth digits.
He also had micropenis. Laryngoscopy and bronchoscopy showed a bifid
uvula and epiglottis with cleft larynx. He subsequently was shown to
have hypopituitarism and a cerebral MRI scan showed a 2 x 2 cm mass in
the hypothalamic region with signal characteristics identical to those
of normal brain tissue. He died suddenly at 9.5 months of age after a
respiratory infection. The father was born with nearly complete 4/5
cutaneous syndactyly of the right hand and postaxial polydactyly of both
hands. He had no other abnormalities. Both parents also had normal
Sama et al. (1994) reported an affected newborn female with a large
suprasellar mass with a posterior cystic component, bilateral choanal
atresia, renal hypoplasia, exomphalos, postaxial polydactyly, and
underdevelopment of the 4th metacarpal. Her father was 38 years old.
Verloes et al. (1995) reported the cases of 2 unrelated, long surviving
patients, aged 2 and 17 years, with Pallister-Hall syndrome. In addition
to hypothalamic hamartoblastoma, both showed mild facial dysmorphism
(downward slanted palpebral fissures, ptosis, microretrognathia), cleft
epiglottis, and developmental delay. The younger child had stenosis of
the pulmonary arteries, complex urogenital malformations, and anal
atresia. The older patient had precocious puberty caused by the
hamartoma, combined with complete growth hormone deficiency. Both
patients showed bony anomalies of the limbs: variable proximal
synostosis between the second to fourth metacarpals or intercalary
polydactyly with generalized brachydactyly, severe brachytelephalangism,
syndactyly, and nail hypoplasia.
The range of phenotypic variability in the Pallister-Hall syndrome may
be demonstrated by the mother and son reported by Low et al. (1995). A
53-year-old woman and her 20-year-old son both presented with
polysyndactyly but without other external malformations or mental
retardation. MRI revealed, as an incidental finding, asymptomatic
hypothalamic hamartomas in both patients. The sibs of both the mother
and the son were unaffected.
Kang et al. (1997) described the clinical characteristics of a family
with a mild form of PHS. Clinical, radiographic, and endoscopic
evaluations showed that the disorder was fully penetrant with variable
expressivity and low morbidity. The proband was a 21-month-old child who
was noted to have ptosis and polydactyly at the time of birth. Cranial
MRI showed a hypothalamic mass compatible with hamartoma. The family
history showed that she had 21 relatives with polydactyly in an
autosomal dominant pattern. The pedigree included 9 obligate
heterozygotes, all of whom had some manifestation of the disorder. The
ratio of males to females was 6 to 16. Several members of the family had
central polydactyly (also referred to as mesoaxial or insertional
polydactyly). This form typically includes partial osseous syndactyly
with proximal fusion of the metacarpals and is characteristic of only a
Galasso et al. (2001) described a boy with Pallister-Hall syndrome with
short stature and growth hormone neurosecretory dysfunction. The patient
was found to have deficient spontaneous growth hormone secretion despite
a normal response to pharmacologic stimulation. The patient responded
positively to long-term growth hormone treatment. Galasso et al. (2001)
concluded that growth hormone deficiency should be considered a cause of
short stature in patients with Pallister-Hall syndrome, especially when
their growth rates decrease.
Autosomal dominant inheritance is supported by the finding of
male-to-male transmission (Kletter and Biesecker, 1992; Topf et al.,
1993; Penman Splitt et al., 1994). Kletter and Biesecker (1992) stated
that the Pallister-Hall syndrome is due to an autosomal dominant gene,
that most cases are sporadic and the result of new mutation, and that
the gene manifests variable expressivity.
Kuller et al. (1992) reported 3 cases. Two of them were affected
brothers, one of whom had a chromosome abnormality: the father was a
balanced carrier for the translocation t(3;7)(p25.3;q36); the offspring
had an unbalanced karyotype with a der(7) chromosome ('7q+'). The
parents, of Filipino extraction, were not known to be related. The
infant, who died at age 5 weeks of necrotizing enterocolitis, had cleft
lip and palate, agenesis of the nasal septum, hypopituitarism by
endocrine evaluation, and fused thalami and a hypothalamic hamartomatous
lesion by MRI. Postaxial polydactyly was not present and the anus was
patent. The older brother died at the age of 3 years. A nonbanded
karyotype performed in the Philippines was said to have been normal.
Micropenis was present in both brothers. Kuller et al. (1992) suggested
that the gene for this disorder may lie on either chromosome 3 or
After conducting a genomewide search with highly polymorphic markers in
4 families with PHS, including 32 affected and 36 unaffected persons,
Kang et al. (1996) found linkage initially to D7S672. Physical mapping
data from this region resulted in refinement of marker order. Genotyping
with additional markers resulted in the maximum 2-point lod score
between PHS and D7S691 of 8.04 at theta = 0.0. Multipoint analysis
showed that the phenotype mapped between D7S521 and D7S678 with a peak
lod score of 13.6 at D7S691. This region contains at least 2 candidate
genes, GLI3 (165240) and inhibin beta-1 (147290). These candidate genes
had previously been mapped to the 7p15-p13 region.
Using anonymous STRP markers in 2 'mildly affected' PHS families, Kang
et al. (1997) established linkage to 7p13 by 2-point analysis with
D7S691, resulting in a lod score of 7.0 at theta = 0.0, near the GLI3
Iafolla et al. (1989) pointed out that magnetic resonance imaging is the
most valuable diagnostic tool; CT scan has been reported to miss the
An international workshop on Pallister-Hall syndrome (Biesecker et al.,
1996) developed minimal diagnostic criteria for this entity. The index
case in a family must have both hypothalamic hamartoma and central
polydactyly to meet the diagnostic criteria. First-degree relatives of
the index case must have either hypothalamic hamartoma or polydactyly
(central or postaxial) and show inheritance in an autosomal dominant
pattern or in a manner consistent with gonadal mosaicism.
Recommendations for clinical evaluation of suspected cases were
presented. Biesecker et al. (1996) concluded that hypothalamic hamartoma
is not specific to PHS.
- Prenatal Diagnosis
Sills et al. (1993) reported Pallister-Hall syndrome in a male infant
and his female sib fetus. Sills et al. (1994) reported that the parents
elected to terminate their third pregnancy because prenatal
ultrasonographic findings suggested PHS. At 12 weeks, ultrasound
demonstrated an abnormal-appearing fetus with large head and a large
midline anterior fluid-filled structure, possibly representing a
dilated, malformed ventricle. Repeat examination at 13 weeks showed
evidence of holoprosencephaly, enlarged cisterna magna, short umbilical
cord, polydactyly, and possible syndactyly. The limbs appeared short. At
termination at 15 weeks, chromosome studies of chorionic villus cells
showed a normal 46,XX karyotype.
- Differential Diagnosis
Verloes et al. (1992) commented that 'Some years ago, syndromologists
and clinical geneticists were pleasantly divided into splitters...and
lumpers...' With the increasing volume of reported congenital anomalies,
they suggested that 2 new categories may be delineated: the
'stretchers,' who are mainly preoccupied with extending the limits of a
given phenotype by adding milder or unusually severe variants, and the
'cut-and-pasters,' who displace the same atypical or borderline cases
from one syndrome to another. Verloes et al. (1992) reviewed the
differential diagnosis of Pallister-Hall syndrome and of syndromal
hypothalamic hamartoblastoma in general. The conditions that they
considered as related included Smith-Lemli-Opitz syndrome (270400), the
pseudotrisomy 13 syndrome or holoprosencephaly-polydactyly syndrome
(264480), orofaciodigital syndrome type VI or Varadi-Papp syndrome
(277170), and the hydrolethalus syndrome (236680). Because of the
insolvable overlap, Verloes et al. (1992) suggested the creation of a
phenotypic classification called the multiplex syndrome, defined as a
clinical frame encompassing an unknown number of genetic and/or
nongenetic multiple congenital anomaly (MCA) syndromes, for which
differential diagnosis cannot be performed unequivocally. They suggested
calling this the cerebroacrovisceral early lethality (CAVE) multiplex
Verloes et al. (1995) described a 24-week-old fetus with agenesis of the
corpus callosum, arhinencephaly, hypothalamic hamartoblastoma, absence
of the right thumb, hypoplastic left thumb, hypoplastic lungs,
intestinal malrotation, microgastria, asplenia, 'inverted' horseshoe
kidney, blind vagina, and absence of internal genitalia.
Underdevelopment of preaxial structures had not previously been reported
in the Pallister-Hall syndrome, in which postaxial polydactyly is a
cardinal feature. Although some features suggested the
'microgastria-limb reduction' complex (156810), patients with that
complex are usually not so severely affected and have never had
associated hypothalamic hamartoblastoma.
Donnai et al. (1987) had suggested that the Pallister-Hall syndrome and
severe Smith-Lemli-Opitz syndrome (270400) are the same disorder. Using
multivariate analysis and numerical taxonomy, Verloes et al. (1995)
concluded that on review, 'most overlapping cases (and, in fact, most
cases reported as Pallister-Hall, including some from the original
report)' could be unambiguously classified as Smith-Lemli-Opitz
syndrome, orofaciodigital syndrome type VI (277170), or
holoprosencephaly-polydactyly syndrome (264480). Together with the
absence of anomalies of cholesterol metabolism, a combination of oral
frenula, laryngeal malformations, digestive abnormalities, intercalary
polysyndactyly, generalized brachytelephalangism, and nail hypoplasia
should allow the delineation of Pallister-Hall syndrome, even when a CNS
tumor is absent (Verloes, 1995). The radiologic abnormalities in the
hand are helpful in differentiating Pallister-Hall syndrome from other
syndromes in which hypothalamic hamartoblastoma is observed. This may be
of major importance for genetic counseling because Pallister-Hall
syndrome is an autosomal dominant disorder, whereas most most of the
other disorders with the CAVE phenotype are recessively inherited.
Because of a possible relationship of PHS to Smith-Lemli-Opitz syndrome,
Biesecker et al. (1996) analyzed levels of cholesterol and intermediate
metabolites of the later stages of cholesterol biosynthesis and found no
evidence of a generalized disorder of cholesterol biosynthesis in
patients with familial PHS. On genetic and biochemical grounds, they
concluded that PHS and Smith-Lemli-Opitz syndrome are not allelic
variants of a single locus.
Unsinn et al. (1995) described a patient who had hydrocolpos and
postaxial polydactyly as well as hypothalamic hamartoblastoma, raising
the possibility that the Pallister-Hall syndrome and the
McKusick-Kaufman syndrome (MKKS; 236700) are one entity. Lurie (1995)
questioned whether the Kaufmann-McKusick syndrome and the Pallister-Hall
syndrome can be considered one entity. Lurie and Wulfsberg (1994) found
in a survey of 43 reported familial cases of MKKS neither preaxial nor
central forms of polydactyly. Lurie (1995) stated that he also did not
remember vaginourethral fistula as occurring in these patients.
Kang et al. (1997) noted that large deletions or translocations
resulting in haploinsufficiency of the GLI3 gene have been associated
with Greig cephalopolysyndactyly syndrome (GCPS; 175700), which maps to
the same region of chromosome 7p, although no mutations in GLI3 were
identified in GCPS patients with normal karyotypes. Both PHS and GCPS
have polysyndactyly and abnormal craniofacial features and are inherited
in an autosomal dominant pattern, but are clinically distinct. The
polydactyly of GCPS is commonly preaxial and that of PHS is typically
central or postaxial. No reported cases of GCPS had hypothalamic
hamartoma and PHS does not cause hypertelorism or broadening of the
nasal root or forehead.
Some patients with PHS have a bifid epiglottis, a rare malformation. On
laryngoscopy in 26 subjects with PHS, Ondrey et al. (2000) found that 15
had a bifid or cleft epiglottis (58%); of 14 subjects with GCPS, which
is also caused by mutation in the GLI3 gene, no instance of cleft
epiglottis was found. Malformed epiglottis was asymptomatic in all of
the prospectively evaluated subjects. One additional PHS subject was
found to have bifid epiglottis and a posterior laryngeal cleft on
autopsy. Ondrey et al. (2000) concluded that bifid epiglottis is common
in PHS, whereas posterior laryngeal clefts are uncommon and occur only
in severely affected patients. They suggested that the diagnosis of a
bifid epiglottis should prompt a thorough search for other sometimes
asymptomatic anomalies of PHS to provide better medical care and
recurrence risk assessment for affected individuals and families.
Because of the colocalization of the loci for PHS and GCPS, Kang et al.
(1997) investigated GLI3 as a candidate gene for PHS. They reported 2
PHS families with frameshift mutations in GLI3 (165240.0002;
165240.0003) located 3-prime of the zinc finger-encoding domains,
including 1 family with a de novo mutation.
Killoran et al. (2000) reported a family in which the proposita was born
with central polydactyly of the right hand, broad thumbs, and short
fingers with hypoplastic nails. She also had a small right kidney,
imperforate anus, and a hypoplastic iliac bone. An older sib with renal
agenesis and polydactyly had died. The mother had polydactyly and
imperforate anus. A maternal aunt had polydactyly, as did the maternal
grandfather. Molecular analysis of the proposita identified a mutation
in the GLI3 gene (165240.0017). The authors noted that subsequent
clinical data showed that the patient had a hypothalamic hamartoma. This
finding and the molecular analysis led to the diagnosis of PHS. Killoran
et al. (2000) stated that they had originally diagnosed their patient
with PIV (polydactyly, imperforate anus, and vertebral anomalies)
syndrome as defined by Say and Gerald (1968). They doubted that the PIV
designation was still useful and suggested that it be viewed as a
historic antecedent to the VACTER/VACTERL association (192350).
Stoll et al. (2001) described a patient considered to have
Pallister-Hall syndrome in which no mutation of the GLI3 mutation could
be detected. The patient had microphallus and no growth hormone
deficiency. He had presented with postaxial polydactyly of the hands,
dysplastic nails, imperforate anus, small penis, scrotum bifidum with
very thin urethra, bifid epiglottis, and a bilateral simian crease.
There was vesicoureteral reflux, insertional hexadactyly of the left
hand, and 2 Y-shaped metacarpals with 6 fingers in the right hand. Brain
MRI revealed a large sellar and suprasellar mass. Bronchoscopy showed
anterior synechia of the vocal cords with cricoid stenosis. A
tracheostomy was performed. Mental development was normal.
Johnston et al. (2005) hypothesized that GLI3 mutations that predict a
truncated functional repressor protein cause Pallister-Hall syndrome,
whereas haploinsufficiency of GLI3 cause Greig cephalopolysyndactyly
syndrome (GCPS; 175700). To test this hypothesis, they screened 46
patients with PHS and 89 patients with GCPS for GLI3 mutations. They
detected 47 pathologic mutations (among 60 probands), and when these
mutations were combined with previously published mutations, 2
genotype-phenotype correlations were evident. GCPS was caused by many
types of alterations, including translocations, large deletions, exonic
deletions and duplications, small in-frame deletions, and missense,
frameshift/nonsense, and splicing mutations. In contrast, PHS was caused
only by frameshift/nonsense and splicing mutations. Among the
frameshift/nonsense mutations, Johnston et al. (2005) found a clear
genotype/phenotype correlation. Mutations in the first third of the gene
(from open reading frame nucleotides 1-1997) caused GCPS, and mutations
in the second third of the gene (from nucleotides 1998-3481) caused
primarily PHS. Surprisingly, there were 12 mutations in patients with
GCPS in the 3-prime third of the gene (after open reading frame
nucleotide 3481), and no patients with PHS had mutations in this region.
These results demonstrated a robust genotype/phenotype correlation for
GLI3 mutations and strongly supported the hypothesis that these 2
allelic disorders have distinct modes of pathogenesis.
Narumi et al. (2010) reported 2 Japanese patients, a 3-year-old girl and
a 10-year-old boy, with PHS and genital anomalies, both of whom had
heterozygous nonsense mutations in the GLI3 gene. The authors reviewed
the 12 previously reported patients with PHS and genital anomalies, all
of whom had nonsense or frameshift mutations in exons 13, 14, or 15 of
GLI3; however, no hotspot for GLI3 mutations was found. In affected
males, hypospadias was observed in 3 patients, micropenis in 2, and
bifid or hypoplastic scrotum in 2. Three also had an anorectal
abnormality (imperforate anus) and 1 had a urologic abnormality (small
kidney). In affected females, all had hydrometrocolpos and/or vaginal
atresia; 2 also had an anorectal abnormality (imperforate anus and
rectoperineal fistula), and 4 had various urologic abnormalities,
including vesicoureteral reflux in 2. Some of these patients had
affected family members with anorectal anomalies and/or rectovaginal
fistula, but no genital abnormalities. Narumi et al. (2010) concluded
that genital features in PHS patients might present a wide range of
severity even among individuals with the same nucleotide change. Noting
that none of the female patients and only 2 of the male patients had
panhypopituitarism, the authors suggested that the urogenital and
anorectal abnormalities might be related to dysregulation of SHH
(600725) signaling rather than hormonal aberrations.
- OMIM diseaseSee_Also: Clarren et al. (1980); Huff and Fernandes (1982)
- OMIM diseaseAllelic_Variants:
- OMIM diseaseCreation_Date: John F. Jackson: 6/15/1995
Victor A. McKusick: 6/2/1986
- OMIM diseaseEdit_History_Data: ckniffin: 05/22/2007
- OMIM diseaseContributors: Ada Hamosh - reviewed: 11/8/2000
Kelly A. Przylepa - revised: 3/16/2000
Marla J. F. O'Neill - updated: 1/26/2012
Carol A. Bocchini - updated: 2/10/2009
Victor A. McKusick - updated: 3/18/2005
Victor A. McKusick - updated: 1/10/2002
Sonja A. Rasmussen - updated: 4/3/2001
Victor A. McKusick - updated: 8/18/1997
Victor A. McKusick - updated: 3/2/1997
Iosif W. Lurie - updated: 1/6/1997
Iosif W. Lurie - updated: 9/19/1996
- OMIM diseaseReference: 1. Biesecker, L. G.; Abbott, M.; Allen, J.; Clericuzio, C.; Feuillan,
P.; Graham, J. M., Jr.; Hall, J.; Kang, S.; Olney, A. H.; Lefton,
D.; Neri, G.; Peters, K.; Verloes, A.: Report from the workshop on
Pallister-Hall syndrome and related phenotypes. Am. J. Med. Genet. 65:
2. Biesecker, L. G.; Kang, S.; Schaffer, A. A.; Abbott, M.; Kelley,
R. I.; Allen, J. C.; Clericuzio, C.; Grebe, T.; Olney, A.; Graham,
J. M., Jr.: Exclusion of candidate loci and cholesterol biosynthetic
abnormalities in familial Pallister-Hall syndrome. J. Med. Genet. 33:
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hamartoblastoma, hypopituitarism, imperforate anus, and postaxial
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4. Donnai, D.; Burn, J.; Hughes, H.: Smith-Lemli-Opitz syndromes:
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A. S.; Bamshad, M. J.; Booth, C.; Curry, C. J.; and 36 others:
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