Clin Genet 2017: 91: 616–622 © 2016 John Wiley & Sons A/S.

Printed in Singapore. All rights reserved Published by John Wiley & Sons Ltd
CLINICAL GENETICS
doi: 10.1111/cge.12872

Short Report

Chromosomal microarray in a highly

consanguineous population: diagnostic yield,
utility of regions of homozygosity, and novel
mutations
Alabdullatif M.A., Al Dhaibani M.A., Khassawneh M.Y., El-Hattab A.W. M.A. Alabdullatifa,† ,
Chromosomal microarray in a highly consanguineous population: diagnostic M.A. Al Dhaibania,† ,
yield, utility of regions of homozygosity, and novel mutations. M.Y. Khassawneha,c
Clin Genet 2017: 91: 616–622. © John Wiley & Sons A/S. Published by and A.W. El-Hattabb
John Wiley & Sons Ltd, 2016 a PediatricsDepartment, b Division of
Chromosomal microarray (CMA) has significantly improved diagnosing Clinical Genetics and Metabolic
copy number variations (CNVs). Single nucleotide polymorphism (SNP) Disorders, Tawam Hospital, Al-Ain, United
Arab Emirates , and c Pediatric
arrays confer additional utility in detecting regions of homozygosity (ROH).
Department, Jordan University of Science
Investigating ROH for genes associated with recessive disorders for and Technology, Jordan
follow-up sequencing can aid in diagnosis. In this study, we performed a
retrospective review of clinical and molecular data for 227 individuals from † These authors have equal contribution.
a highly consanguineous population who previously had a CMA. Pathogenic
CNVs were identified in 32 (14%) cases; ROH suggesting uniparental
disomy (UPD) in three (1%) cases, and an additional 25 (11%) individuals Key words: chromosomal microarray –
were diagnosed with recessive disorders caused by mutations in ROH regions of homozygosity –
consanguinity – autosomal recessive
candidate genes, thereby increasing the CMA diagnostic yield to 26%.
diseases – novel gene mutations
Among the 25 individuals with recessive diseases, 18 had novel mutations in
16 genes (ASPM, SPINK5, QARS, MEGF10, SPATA7, GMPPA, ABCA4, Corresponding author: Ayman W.
SRD5A2, RPGRIP1L, MET, SLC12A6, ALDH1A3, TNFRSF11A, FLNB, El-Hattab, MD, FAAP, FACMG, Division
PHGDH, and FKBP10) including five with phenotypic expansion. of Clinical Genetics and Metabolic
Disorders, Tawam Hospital, P.O. Box
Conflict of interest 15258, Al-Ain, United Arab Emirate.
Tel.: +971508875123;
The authors declare that they have no conflict of interest. fax: +9713-707-2731
e-mail: elhattabaw@yahoo.com

Received 18 August 2016, revised and

accepted for publication 17 September
2016

Chromosomal microarray (CMA) has significantly
improved the accuracy and yield of diagnosing copy
number variations (CNVs). It has been routinely
used as a first-tier diagnostic test for individuals
with neurodevelopmental disabilities or congeni-
tal anomalies (1). CMA offers a diagnostic yield of
10%–20% (1, 2) for pathogenic CNVs which can be
detected by either comparative genomic hybridization
(CGH) arrays or single nucleotide polymorphism (SNP)
arrays (3).
In addition to the ability of detecting CNVs, SNP
arrays can reveal regions of homozygosity (ROH) in
the genome which may indicate ancestral relatedness,
uniparental disomy (UPD), or parental blood relationship
(consanguinity) (4). Short ROH (<5 Mb) indicate ances-
tral homozygosity in an outbred population. A single
large ROH or multiple ROH on the same chromosome
likely indicates UPD. Multiple large ROH on different
chromosomes likely represent parental consanguin-
ity. Based on inbreeding coefficient, the fractions of
the genome that are covered by ROH are calculated
to be 12.5%, 6%, and 1.5% when parents are dou-
ble first cousins, first cousins, and second cousins,
respectively (4).

616
 Chromosomal microarray in a highly consanguineous population
The detection of ROH is not diagnostic of any specific
disease. However, such findings can be useful in clinical
diagnostics by guiding additional genetic testing. When
UPD is suspected based on the ROH findings, methy-
lation analysis is needed to diagnose a UPD syndrome
(5). Analysis of ROH can also aid in diagnosing autoso-
mal recessive disorders in consanguineous families by
enabling prioritization of genes mapping to ROH and
associated with recessive diseases that could explain the
phenotype for follow-up sequencing (6). The autozy-
gosity mapping approach has been effectively used in
consanguineous populations both in clinic to prioritize
recessive candidate genes and in research to discover
novel disease-causing genes (6, 7).
In this study, we perform a retrospective review of
clinical and molecular data for 227 individuals from
a highly consanguineous population who underwent
a combined (CGH+SNP) CMA test. We present the
overall diagnostic yield of CMA. We also demonstrate
how investigating ROH aided in increasing the diagnostic
yield of CMA and identifying several novel mutations
some of which are associated with phenotypic expansion.
Methods
This study included all individuals who were evalu-
ated by clinical geneticists in Tawam Hospital, Al-Ain,
United Arab Emirates, and had CMA during the year
2015. We retrospectively reviewed medical records for
clinical data, consanguinity status, and results of CMA
and other genetic tests. The study was approved by
Al-Ain Medical District Human Research Ethics Com-
mittee. CMA was performed at Prevention Genetics
using CGH + SNP CMA manufactured by Agilent tech-
nologies, Inc. (Santa Clara, CA). This CMA (ISCA
4X180K, Design ID-029830) contains 180,000 oligonu-
cleotide probes, of which 110,712 are copy number
probes, and 59,647 are SNP probes. The overall back-
bone median probe spacing was 25 kb with a higher res-
olution (5 kb) within targeted regions. The SNP probes
provide an average 5 Mb resolution for ROH detection.
The genomic build hg19 was used. ROH identified on
CMA were reviewed for genes associated with reces-
sive diseases that would explain the phenotype reported
in tested individuals. The candidate genes were then
reviewed by the clinical geneticist who subsequently
requested follow-up single-gene Sanger sequencing,
multi-gene panel next generation sequencing (NGS), or
whole exome sequencing (WES) based on the clinical
phenotype, candidate gene list, test availability, and cost.
Results
CMA was performed in 227 individuals, including 14
adults (20–41 years, mean 30.8 years) and 213 chil-
dren (3 days–16 years, mean 3.9 years). Consanguin-
ity was reported in 165 (73%) individuals (Table S1,
Supporting Information). Out of 227 individuals, 150
(66%) had cognitive impairment, 144 (63%) had dis-
tinctive facial features, and 103 (45%) had neurolog-
ical manifestations. Gastrointestinal, ophthalmological,
cardiovascular, and respiratory complaints were also
common (Table S2). CMA identified pathogenic CNVs
in 14% (32/227) of cases including 23 individuals with
microdeletion/duplication syndromes, four individuals
with deletion/duplication indicating unbalanced translo-
cations, and five individuals with CNVs affecting single
genes resulting in Mendelian diseases (Tables 1 and S3).
ROH was reported in 78% (176/227) of cases with a
mean ROH fraction of 4.9% (0.3%–16.8%). ROH sug-
gested UPD in 1% (3/227) of cases (Tables 1 and S4).
After exclusion of individuals with UPD and CNVs,
the remaining 157 individuals with ROH were inves-
tigated for genes associated with recessive disorders
that would explain the phenotype in tested individuals.
Among these 157 cases, candidate genes were identified
in 77 (49%) individuals. The number of candidate genes
for each case usually ranged from 1–4, with 52% (40/77)
of these having only one candidate gene. Among the
77 individuals with identified ROH candidate genes, 59
underwent follow-up testing (42 had Sanger sequencing
or multi-gene panel NGS and 17 had WES). Homozy-
gous mutations in ROH candidate genes were identified
in 25 individuals (15 with Sanger sequencing or NGS
and 10 with WES) among whom 18 had novel mutations
including five with phenotypic expansion (Tables 1 and
S5). Therefore, ROH investigation aided in diagnosing
42% (25/59) of those who had follow-up testing and
resulted in an additional 11% (25/227) diagnostic yield
of CMA, thereby increasing the CMA total diagnostic
yield to 26% (Fig. 1).
Discussion
Herein we present the CMA diagnostic outcome for indi-
viduals from a highly consanguineous population. The
diagnostic yield of CNVs in this cohort is consistent with
previous reports. Among the 32 individuals with CNVs,
23 had microdeletion/duplication syndromes including
one with two deletions. Individual 196 was a 4-year-old
girl with developmental delay, joint hyperlaxity, and
growth failure who was found to have both 2p14
and 12q24.33 deletions. Her mother who had intel-
lectual disability was found to carry the same dele-
tions. These two deletions have been reported in indi-
viduals with cognitive impairment (8, 9). Unbalanced
translocations were observed in four individuals (7q;9p,
2q;11q, 5p;Xp, and Yq:18p). Individual 205 was an adult
female who presented with primary amenorrhea and
short stature and found to have 5p15.33-p13.3 duplica-
tion and Xp22.33-p11.21 deletion (5p;Xp translocation).
The observed Turner-like phenotype in this individual
is due to the chromosome Xp terminal deletion. CNVs
affecting single genes have resulted in Mendelian dis-
eases in five individuals including individual 100 who
presented with congenital diarrhea and duodenal biopsy
highly suggestive of tufting enteropathy. At the age of
3 years, he developed medulloblastoma. CMA showed a
2p21 homozygous deletion encompassing both EPCAM
and MSH2, revealing the diagnosis of both autosomal
recessive diseases: tufting enteropathy and mismatch
repair cancer syndrome (Tables 1 and S3).
617
Alabdullatif et al.
Table 1. Summary of the chromosomal microarray diagnostic results
CNVs
Microdeletion/duplication syndromes
001 17p13.3 duplication (254 Kb; 963,697-1,218,123)
026 17p11.2 duplication (3.44 Mb; 16,782,546-20,219,464)
035 11p14.1-p15.5 duplication (30.2 Mb; 196,966-30,453,791)
050 1p36.33-p36.32 deletion (2.4 Mb; 746,608-3,161,082)
053 17p13.3 duplication (260 Kb; 954,938-1,218,123)
060 15q13.2q13.3 deletion (1.55 Mb; 30,954,726-32,509,926)
064 22q11.21 deletion (2.8 Mb; 18,661,724-21,505,417)
070 Xq28 duplication (4.7 Mb; 149,983,491-154,664,396)
073 3q24-q26.1 deletion (12.8 Mb; 148,603,883-161,449,432)
087 7q11.23 deletion (1.5 Mb; 72,726,572-74,285,345)
091 8p23.1 deletion (4.7 Mb; 7,169,490-11,860,230)
097 3q27.1-q28 deletion (7.8 Mb; 182,924,113-190,712,883).
105 9p13.3-p13.1 deletion (5.9 Mb; 33,388,612-39,254,388)
124 4p16.3-p16.1 deletion (8.5 Mb; 72,447-8,607,464)
153 15q11.2-q13.1 deletion (5.9 Mb; 22,765,628-28,691,460)
162 10q25.2-q26.3 duplication (22 Mb;
112,880,350-135,434,178)
164 8p23.1 duplication (1.64 Mb; 10,828,352-12,467,543)
165 7q11.22-q21.11 deletion (11 Mb; 71,300,290-82,294,906)
177 10q26.2-q26.3 deletion (6.9 Mb; 128,349,331-135,234,843)
183 18q22.3q23 deletion (6.4 Mb 71,633,081-78,012,829)
189 15q11.2-q13.1 deletion (5.8 Mb; 22,765,628-28,559,402)
196 2p14 deletion (2.6 Mb; 65,398,083-68,023,402) 12q24.33
deletion (80 kb; 133,306,501- 133,386,915)
213 17q21.31 duplication (695 Kb; 42,875,129-43,570,427)
Unbalanced translocations
101 7q35-q36.3 duplication (13 Mb; 146,164,539-159,128,556)
9p24.3-p22.3 deletion (14 Mb; 204,193-14,628,305)
(unbalanced 7q;9p translocation)
167 2q37.2-q37.3 deletion (7.0 Mb; 236,057,247-243,040,276)
11q23.3-q25 duplication (15.4 Mb;
119,576,902-134,934,196) (unbalanced 2q;11q
translocation)
205 5p15.33-p13.3 duplication (33.7 Mb; 22,149-33,702,845)
Xp22.33-p11.21 deletion (57.8 Mb; 60,701-57,857,211)
(unbalanced 5p;Xp translocation)
216 18p11.32-p11.21 deletion (14.9 Mb; 148,963-15,072,794)
Yq12 terminal duplication (30.2 Mb;
28,804,482-59,020,077) (unbalanced Yq:18p translocation)
Mendelian (single-gene) disorders
027 Xq21.1 duplication (22 Kb; 76,992,100-77,014,098 within the
MAGT1 gene)
085 Xp22.33 duplication (276 kb; 423,597-699,424; including
SHOX gene)
086 16p13.3 deletion (1.4 Mb; 3,828,398-5,219,398; including
CREBBP gene)
100 2p21 homozygous deletion (81 kb; 47,584,496-47,665,383;
including EPCAM and MSH2)
160 3p14.1p13 deletion (738 kb; 69,576,082-70,313,620;
including MITF gene)
UPD
068 Segmental UPD 7: 7p11.2q21.3 (39.4 Mb;
55,501,248-94,900,975) and 7q32.1q36.1 (20.1 Mb;
129,103,147-149,204,690)
199 UPD 14q24.3-q32.33 (32 Mb; 75,040,338-107,187,899)
203 UPD 15q14-q21.3 (16.7 Mb; 39,011,297-55,810,711)
618
Split-hand/foot malformation with long bone deficiency 3
[MIM:612576]
Potocki–Lupski syndrome [MIM:610883]
Beckwith–Wiedemann syndrome [MIM:130650]
Chromosome 1p36 deletion syndrome [MIM:607872]
Split-hand/foot malformation with long bone deficiency 3
[MIM:612576]
Chromosome 15q13.3 deletion syndrome [MIM:612001]
DiGeorge syndrome [MIM:188400]
Chromosome Xq28 duplication syndrome [MIM:300815]
Chromosome 3q24q26.1 deletion
Williams–Beuren syndrome [MIM:194050]
Chromosome 8p23.1 deletion syndrome
Chromosome 3q27.1-q28 deletion
Chromosome 9p13.3-p13.1 deletion
Wolf–Hirschhorn syndrome [MIM:194190]
Prader–Willi syndrome [MIM:176270]
Chromosome 10q distal trisomy syndrome
Chromosome 8p23.1 duplication syndrome
Williams–Beuren syndrome [MIM:194050]
Chromosome 10q26.2-q26.3 deletion
Chromosome 18q deletion syndrome [MIM:601808]
Prader–Willi syndrome [MIM:176270]
Chromosomes 2p14 deletion and chromosome 12q24.33
deletion
Chromosome 17q21.31 duplication syndrome [MIM:61353]
Chromosome 7q35-q36.3 duplication and chromosome
9p24.3-p22.3 deletion
Chromosome 2q37 deletion syndrome [MIM:600430] and
chromosome 11q partial trisomy
Chromosome Xp terminal deletion (Turner phenotype)
Chromosome 18p deletion syndrome [MIM:146390]
Immunodeficiency, X-linked, with magnesium defect, EBV
infection and neoplasia [MIM:300853]
Short stature, X-linked [MIM:300582]
Rubinstein–Taybi syndrome [MIM:180849]
Tufting enteropathy [MIM:613217] & mismatch repair
cancer syndrome [MIM:276300]
Waardenburg syndrome, type 2A [MIM:193510]
Silver–Russell syndrome, chromosome 7 related
[MIM:180860]
Temple syndrome [MIM:616222]
Angelman syndrome [MIM:105830]
 Chromosomal microarray in a highly consanguineous population
Table 1. Continued
ROH candidate genes
Novel mutations
003 Novel splice-site homozygous mutation (c.9084+5G>T) in
ASPM [MIM:605481]
006 Novel homozygous splice-site mutation (c.882+2T>C) in
SPINK5 [MIM:605010]
011 Novel homozygous missense mutation c.1058G>T
(p.Gly353Val) in QARS [MIM:603727]
014 Novel homozygous frameshift mutation c.1557delA
(p.Trp520fs) in MEGF10 [MIM:612453]
032 Novel homozygous nonsense mutation c.288T>A (p.Cys96*)
in SPATA7 [MIM:609868]
037 Novel homozygous missense mutation c.922G>A
(p.Gly308Arg) in GMPPA [MIM:615495]
082 Novel homozygous frameshift mutation c.749delT
(p.Phe250fs) in ABCA4 [MIM:601691]
090 Novel homozygous missense mutation c.354C>A
(p.Phe118Leu) in SRD5A2 [MIM:607306]
141 Novel homozygous splice-site mutation c.1582-1G>C in
RPGRIP1L [MIM:610937]
145 Novel homozygous missense mutation c.3557T>G
(p.Phe1186Cys) in MET [MIM:164860]
146 Novel homozygous missense mutation c.3557T>G
(p.Phe1186Cys) in MET [MIM:164860]
155 Novel homozygous splice-site mutation c.745+2T>A in
SLC12A6 [MIM:604878]
158 Novel homozygous missense mutation c.845G>C
(p.Gly282Ala) in ALDH1A3 [MIM:600463]
159 Novel homozygous missense mutation c.845G>C
(p.Gly282Ala) in ALDH1A3 [MIM:600463]
169 Novel homozygous missense mutation c.400G>A
(p.Ala134Thr) in TNFRSF11A [MIM:603499]
181 Novel homozygous nonsense mutation c.4545T>A
(p.Tyr1515*) in FLNB [MIM: 603381]
209 Novel homozygous missense mutation c.1286G>T
(p.Gly429Val) in PHGDH [MIM:606879]
210 Novel homozygous frameshift mutation c.354delT
(p.Ile118Metfs*41) in FKBP10 [MIM:607063]
Previously reported mutations
093 Homozygous splice-site mutation c.606-1G>A in WWOX
[MIM:605131]
115 Homozygous splice-site mutation c.232+1G>A in CA2
[MIM:611492]
121 Homozygous mutation c.71A>G in RMPR [MIM:157660]
186 Homozygous missense mutation c.682C>T (p.Arg228Cys) in
ALDH3A2 [MIM:609523]
194 Homozygous missense mutation c.315G>C (p.Glu105Asp) in
TPI1 [MIM:190450]
207 Homozygous splice-site mutation c.351-9T>C in CHRNG
[MIM:100730]
227 Homozygous frameshift mutation c.831dupC
(p.Gly278Argfs*95) in FKBP10 [MIM:607063]
Although CMA was able to diagnose 14% of this
cohort with CNVs, the larger fraction did not have
CNVs. During the diagnostic odyssey, individuals with
normal CMA typically undergo additional evaluation
for diseases caused by other molecular mechanisms
such as single-gene mutations, imprinting defects,
Microcephaly 5, primary, autosomal recessive
[MIM:608716]
Netherton syndrome [MIM:256500]
Microcephaly, progressive, seizures, and cerebral and
cerebellar atrophy [MIM:615760]
Myopathy, areflexia, respiratory distress, and dysphagia,
early-onset (EMARDD) [MIM:614399]
Leber congenital amaurosis 3 [MIM:604232]
Alacrima, achalasia, and mental retardation syndrome
[MIM:615510]
Stargardt disease 1 [MIM:248200]
5 alpha reductase deficiency [MIM:264600]
COACH syndrome [MIM:216360]
Deafness, autosomal recessive 97 [MIM:616705]
Deafness, autosomal recessive 97 [MIM:616705]
Agenesis of the corpus callosum with peripheral
neuropathy [MIM:218000]
Microphthalmia, isolated 8 [MIM:615113]
Microphthalmia, isolated 8 [MIM:615113]
Osteopetrosis, autosomal recessive 7 [MIM:612301]
Spondylocarpotarsal synostosis syndrome [MIM:272460]
Phosphoglycerate dehydrogenase deficiency [MIM:601815]
Bruck syndrome 1 [MIM:259450]
Epileptic encephalopathy, early infantile, 28 [MIM:616211]
Osteopetrosis, autosomal recessive 3, with renal tubular
acidosis [MIM:259730]
Cartilage-hair hypoplasia [MIM:250250]
Sjogren–Larsson syndrome [MIM:270200]
Hemolytic anemia due to triosephosphate isomerase
deficiency [MIM:615512]
Multiple pterygium syndrome, Escobar variant
[MIM:265000]
Osteogenesis imperfecta, type XI [MIM:610968]
and repeat expansions. Current follow-up strategy
for detection of point mutations includes single-gene
Sanger sequencing, multi-gene panel NGS, WES, or
whole-genome sequencing. While the effectiveness of
different sequencing approaches depends on the clinical
condition and genetic heterogeneity, the diagnostic
619
Alabdullatif et al.
Fig. 1. Diagram demonstrating the number of individuals in each diag-
nostic category.
utility of WES has been well established (10). Despite
its high diagnostic yield and increasing adoption in
clinical practice, WES remains cost-prohibitive with
long turn-around times.
In this study, we attempted to maximize the utility
of CMA by investigating the ROH in a highly con-
sanguineous population. In consanguineous families,
the risk of autosomal recessive diseases is higher with
increased probability of homozygous disease alleles
residing within ROH (11). Investigating genes in these
ROH can aid the diagnosis of recessive disorders. While
studies of cohorts with low consanguinity showed very
low yield of such methodology (12, 13), other studies
have demonstrated the utility of autozygosity mapping
in high consanguineous populations (6, 7). In our high
consanguineous cohort investigating the ROH resulted
in identifying candidate genes in half of the cases with
ROH. Many of these cases had only one candidate gene,
thus making it easier and more cost-effective to request
single-gene follow-up sequencing. For the individuals
with suggested candidate genes who had follow-up
testing, about 40% were diagnosed to have recessive
620
diseases caused by homozygous mutations in one of the
ROH candidate genes. This approach not only added
11% to the overall diagnostic yield of CMA, but can
also result in cost-reduction and time-saving when com-
pared to the alternative approach of performing WES.
On the other hand, the observed increased CMA yield
through ROH investigation is likely to be underestimated
because not all individuals with ROH candidate genes
had follow-up tests. In addition, the CMA platform
used to test these individuals has an average resolution
for ROH detection of 5 Mb; therefore, smaller ROH
can be missed.
The 25 individuals diagnosed with recessive diseases
caused by ROH candidate genes included 18 individuals
with novel mutations in 16 genes (ASPM, SPINK5,
QARS, MEGF10, SPATA7, GMPPA, ABCA4, SRD5A2,
RPGRIP1L, MET, SLC12A6, ALDH1A3, TNFRSF11A,
FLNB, PHGDH, and FKBP10) (Tables 1 and S5). In
eight families with novel mutations, segregation studies
were performed and further supported the pathogenic-
ity of these mutations (Fig. 2). Phenotypic expansion
was observed in five individuals with novel mutations.
Individual 011 was an 11-year-old boy with cognitive
impairment, microcephaly, growth failure, nystag-
mus, and hypotonia who was found to carry the novel
homozygous mutation c.1058G>T (p.G353V) in QARS,
confirming the diagnosis of progressive microcephaly,
seizures, and cerebral and cerebellar atrophy syndrome.
Although seizures and cerebellar atrophy are essen-
tial features of this syndrome (14), the child reported
here only had febrile convulsions that resolved and a
normal brain MRI, indicating that these two findings
can be variable in this syndrome. This child had nine
healthy siblings, none of whom were homozygous for
the p.G353V, thus supporting the pathogenicity of this
mutation (Fig. 2). In silico, this mutation was predicted
to be deleterious by both SIFT and Polyphen-2. Individ-
uals 145 and 146 were brothers who both had hearing
loss and arthrogryposis. The novel homozygous muta-
tion c.3557T>G (p.F1186C) in MET was identified in
both. This mutation was predicted to be deleterious by
both SIFT and Polyphen-2. Biallelic mutations in this
gene have been reported in individuals with autosomal
recessive deafness type 97 (15). The arthrogryposis in
these brothers could be a variable feature of this newly
described disease or due to the presence of a second
recessive disease. Individual 155 was an 11-year-old
female with cognitive impairment, hypotonia, weakness,
ataxia, foot deformities, kyphoscoliosis, hyporeflexia,
decreased sensation, distinctive facial features, and
demyelinating polyneuropathy. The novel homozygous
splice-site mutation c.745+2T>A was identified in
SLC12A6 confirming the diagnosis of agenesis of the
corpus callosum with peripheral neuropathy syndrome.
Although corpus callosum involvement is part of this
syndrome (16), this child had a normal brain MRI
indicating that corpus callosum agenesis can be a vari-
able feature in this syndrome. Individual 169 was a
1.5-year-old boy with external hydrocephalus, develop-
mental delay, bilateral optic atrophy, epilepsy, growth
failure, distinctive facial features, and osteopetrosis. A
 Chromosomal microarray in a highly consanguineous population
Fig. 2. Pedigrees for families of individuals 011, 014, 032, 082, 090, 145, 146, 155, 158, and 159. +/+ indicates homozygosity for the mutation,
+/− indicates heterozygosity for the mutation, and −/− means that the subject does not carry the mutation.
novel homozygous mutation c.400G>A (p.A134T) in
TNFRSF11A was identified changing an amino acid at
moderately conserved position and supporting the diag-
nosis of autosomal recessive osteopetrosis type 7 (17).
The neurological manifestations in this child could be
previously unrecognized features of this syndrome or due
to the presence of a second recessive disease (Tables 1
and S5).
In conclusion, investigation of ROH to identify can-
didate genes for follow-up sequencing can increase the
clinical utility of CMA in a highly consanguineous pop-
ulation. We suggest utilizing this alternative approach
to leverage all available information from CMA before
obtaining WES.
Supporting Information
Additional supporting information may be found in the online
version of this article at the publisher’s web-site.
Acknowledgements
We thank Pilar Magoulas for reading an earlier version of this
manuscript. We also thank Gina Londre, Srirangan Sampath, and
Elizabeth McPherson for their help and advice while writing this
manuscript.
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